Personalized immunotherapy against several neuronal and brain tumors

ABSTRACT

The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to British Patent Application No,1319446.9 and U.S. Patent Application No. 61/899,680, both filed Nov. 4,2013, the contents of which are incorporated herein by reference intheir entireties. This application is also a continuation ofPCT/EP2014/073588, filed Nov. 3, 2014, the contents of which are alsoincorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

The present invention relates to peptides, nucleic acids and cells foruse in immunotherapeutic methods. In particular, the present inventionrelates to the immunotherapy of cancer. The present inventionfurthermore relates to tumor-associated cytotoxic T cell (CTL) peptideepitopes, alone or in combination with other tumor-associated peptidesthat serve as active pharmaceutical ingredients of vaccine compositionsthat stimulate anti-tumor immune responses. The present inventionrelates to specific peptide sequences and their variants derived fromHLA class I and class II molecules of human tumor cells that can be usedin vaccine compositions for eliciting anti-tumor immune responses aswell as a method for providing optimal vaccines to persons in need.

2. Description of Related Art

Gliomas are brain tumors originating from glial cells in the nervoussystem. Glial cells, commonly called neuroglia or simply glia, arenon-neuronal cells that provide support and nutrition, maintainhomeostasis, form myelin, and participate in signal transmission in thenervous system. The two most important subgroups of gliomas areastrocytomas and oligodendrogliomas, named according to the normal glialcell type from which they originate (astrocytes or oligodendrocytes,respectively). Belonging to the subgroup of astrocytomas, glioblastomamultiforme (referred to as glioblastoma hereinafter) is the most commonmalignant brain tumor in adults and accounts for approx. 40% of allmalignant brain tumors and approx. 50% of gliomas. It aggressivelyinvades the central nervous system and is ranked at the highestmalignancy level (grade IV) among all gliomas. Although there has beensteady progress in their treatment due to improvements in neuroimaging,microsurgery, diverse treatment options, such as temozolomide orradiation, glioblastomas remain incurable. The lethal rate of this braintumor is very high: the average life expectancy is 9 to 12 months afterfirst diagnosis. The 5-year survival rate during the observation periodfrom 1986 to 1990 was 8.0%. To date, the five-year survival ratefollowing aggressive therapy including gross tumor resection is stillless than 10%. Accordingly, there is a strong medical need for analternative and effective therapeutic method.

Tumor cells of glioblastomas are the most undifferentiated ones amongbrain tumors, so the tumor cells have high potential of migration andproliferation and are highly invasive, leading to very poor prognosis.Glioblastomas lead to death due to rapid, aggressive, and infiltrativegrowth in the brain. The infiltrative growth pattern is responsible forthe unresectable nature of these tumors. Glioblastomas are alsorelatively resistant to radiation and chemotherapy, and, therefore,post-treatment recurrence rates are high. In addition, the immuneresponse to the neoplastic cells is rather ineffective in completelyeradicating all neoplastic cells following resection and radiationtherapy.

Glioblastoma is classified into primary glioblastoma (de novo) andsecondary glioblastoma, depending on differences in the gene mechanismduring malignant transformation of undifferentiated astrocytes or glialprecursor cells. Secondary glioblastoma occurs in a younger populationof up to 45 years of age. During 4 to 5 years, on average, secondaryglioblastoma develops from lower-grade astrocytoma throughundifferentiated astrocytoma. In contrast, primary glioblastomapredominantly occurs in an older population with a mean age of 55 years.Generally, primary glioblastoma occurs as fulminant glioblastomacharacterized by tumor progression within 3 months from the state withno clinical or pathological abnormalities (Pathology and Genetics of theNervous Systems. 29-39 (IARC Press, Lyon, France, 2000)).

Glioblastoma migrates along myelinated nerves and spreads widely in thecentral nervous system. In most cases surgical treatment shows onlylimited sustainable therapeutic effect. Malignant glioma cells evadedetection by the host's immune system by producing immunosuppressiveagents that impair T cell proliferation and production of theimmune-stimulating cytokine IL-2.

Intracranial neoplasms can arise from any of the structures or celltypes present in the CNS, including the brain, meninges, pituitarygland, skull, and even residual embryonic tissue. The overall annualincidence of primary brain tumors in the United States is 14 cases per100,000. The most common primary brain tumors are meningiomas,representing 27% of all primary brain tumors, and glioblastomas,representing 23% of all primary brain tumors (whereas glioblastomasaccount for 40% of malignant brain tumor in adults). Many of thesetumors are aggressive and of high grade. Primary brain tumors are themost common solid tumors in children and the second most frequent causeof cancer death after leukemia in children.

The search for effective treatment of glioblastomas in patients is stillongoing today. Immunotherapy or treatment via recruitment of the immunesystem, to fight these neoplastic cells has been investigated.

There is an ongoing clinical trial with IMA950, a multi-peptide vaccineconducted in the UK by immatics biotechnologies (Tübingen, Germany). Thepeptides in the vaccine are exclusively HLA-A*02 peptides.

There remains a need for new efficacious and safe treatment option forglioblastoma and medulloblastoma and other tumors which show anoverexpression of the proteins of the present invention, enhancing thewell-being of the patients with other HLA alleles or combinations ofalleles without using chemotherapeutic agents or other agents which maylead to severe side effects.

SUMMARY

In a first aspect of the present invention, the present inventionrelates to a peptide comprising an amino acid sequence selected from thegroup of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74to 129, and variant sequences thereof which are at least 90% homologousto SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to129, and wherein said variant induces T cells cross-reacting with saidpeptide; or a pharmaceutical acceptable salt thereof, wherein saidpeptide is not a full-length polypeptide.

The present invention further relates to a peptide of the presentinvention, comprising a sequence that is selected from the group of SEQID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, andvariant sequences thereof which are at least 90% homolog to SEQ ID No. 1to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, wherein saidpeptide or variant has an overall length of between 8 and 100,preferably between 8 and 30, and most preferred between 8 and 14 aminoacids.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1: Exemplary mass spectrum from IGF2BP3-001 demonstrating itspresentation on primary tumor sample glioblastoma. NanoESI-LCMS wasperformed on a peptide pool eluted from the glioblastoma sample 6010.The mass chromatogram for m/z 536.3229±0.001 Da, z=2 shows a peptidepeak at the retention time 48.76 min. B) The detected peak in the masschromatogram at 48.76 min revealed a signal of m/z 536.3229 in the MSspectrum. C) A collisionally induced decay mass spectrum from theselected precursor m/z 536.3229 recorded in the nanoESI-LCMS experimentat the given retention time confirmed the presence of IGF2BP3-001 in theglioblastoma 6010 tumor sample. D) The fragmentation pattern of thesynthetic IGF2BP3-001 reference peptide was recorded and compared to thegenerated natural TUMAP fragmentation pattern shown in C for sequenceverification.

FIG. 2: Expression profiles of mRNA of selected proteins in normaltissues and in 22 glioblastoma cancer samples. a) CSRP2 (Probeset ID:211126_s_at); b) PTPRZ1 (Probeset ID: 204469_at).

FIG. 3: Presentation profiles for selected HLA class I peptides. Apresentation profile was calculated for each peptide showing the meansample presentation as well as replicate variations. The profilejuxtaposes samples of the tumor entity of interest to a baseline ofnormal tissue samples. a) CSRP2-001 (HLA-A*02); b) PTP-012 (HLA-A*02);c) TMEM255A-001 (HLA-A*24); d) PJA2-001 (HLA-A*24).

FIG. 4: Exemplary results of peptide-specific in vitro immunogenicity ofclass I TUMAPs for HLA*A02 and HLA*A24. Specific CD8+ T cells werestained with HLA multimers each linked to two different fluorochromes.Dot plots show MHC multimer-double-positive populations for thestimulating peptides (left panels) and the respective negative controlstimulations (right panels).

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The following tables show the peptides according to the presentinvention, their respective SEQ ID NO, and the prospective sourceproteins for these peptides. All peptides in Tables 1a, 1b and 1c bindto the HLA-A*02 allele, peptides in Table 1d and 1e bind to HLA-DRalleles.

The class II peptides in table 1d and 1e are particularly useful in thetreatment of cancers over-expressing and/or over-presenting thepolypeptides BCAN, BIRC5 and/or PTPRZ1.

TABLE 1a Peptides of the present invention SEQ ID Source NO:Peptide Code Sequence Protein(s) 1 CSRP2-001 RLGIKPESV CSRP2 2SLC10A4-001 ALAFKLDEV SLC10A4 3 ELOVL2-001 YLPTFFLTV ELOVL2 4 MTSS1L-001GLPSGAPPGV MTSS1L 5 PTP-013 MIWEHNVEV PTPRZ1 6 KIF1A-001 LLWGNAIFL KIF1A7 PCDHGC5-001 GLDPSSGAIHV PCDHGC5 8 GRIK3-001 LLYDAVHIV GRIK3 9SEZ6L-001 LLLGSPAAA SEZ6L 10 ANKRD40-001 ALGDIREV ANKRD40 11 NLGN4Y-001SLDTLMTYV NLGN4Y 12 KCN-002 ALSVRISNV KCNJ10 13 BCA-003 FLWSDGVPL BCAN14 MAGI2-001 AVAPGPWKV MAGI2 15 PTP-012 FLLPDTDGLTAL PTPRZ1 16SCARA3-001 SLGLFLAQV SCARA3 17 GRI-002 VLIQDVPTL GRIA4 18 CLU-001KLFDSDPITVTV CLU 19 CERS1-001 FLHDISDVQL CERS1 20 SLC10A4-002 RVADYIVKVSLC10A4 21 GPR98-001 ALFNKGGSVFL GPR98 22 GYG2-001 KVFDEVIEV GYG2 23CPT1C-001 GLMEKIKEL CPT1C 24 SLC35E1-002 GMMTAILGV SLC35E1 25 PTP-002FLYKVILSL PTPRZ1 26 PTP-001 ALTTLMHQL PTPRZ1 27 ASIC4-001 EILDYIYEVASIC4 28 COL20-001 FLVDGSWSI COL20A1 29 EGFR-008 YQDPHSTAV EGFR 30JAK-001 KLTDIQIEL JAKMIP2/JAKMIP3 31 WLS-002 TMMSRPPVL WLS/MIER1 32IRS-001 RVAS*PTSGV IRS2 33 NAT8L-001 SLAERLFFQV NAT8L 34 TNC-001AMTQLLAGV TNC 35 MAP1B-002 GLSEFTEYL MAP1B 36 NCAN-001 VLCGPPPAV NCAN 37ADORA3-001 ALADIAVGV ADORA3 38 NPAS3-001 LLYTGDLEAL NPAS3 39 NLGN4X-002GLLDQIQAL NLGN4Y/NLGN3/N LGN4X/NLGN2 40 GRI-001 NILEQIVSV GRIA4 41DPP3-001 FLYNEALYSL DPP3/BBS1 S* = optionally phosphorylated serine

TABLE 1b Additional peptides of the present invention SEQ ID Source NO:Peptide Code Sequence Protein(s) 42 USP11-001 MLFGHPLLVSV USP11 43EIF4E-001 RLISKFDTV EIF4E 44 PLEKHA4-001 LLQDRLVSV PLEKHA4 45 CCT-001TLLAAEFLKQV CCT7 46 NOC4-001 LTAPPEALLMV NOC4L 47 MAP1B-001 FLDSKFYLLMAP1B 48 CHCHD2-005 KLCEGFNEV CHCHD2 49 SOX-001 KLADQYPHLSOX8/SOX9/SOX10

TABLE 1c Additional peptides that are over- expressed in glioblastomaSEQ ID Source NO: Peptide Code Sequence Protein(s) 50 PTP-005 KVFAGIPTVPTPRZ1 51 BCA-002 ALWAWPSEL BCAN 52 CDK4-001 TLWYRAPEV CDK4/CDK6 53MAGEF1-001 ILFPDIIARA MAGEF1 54 PTP-003 AIIDGVESV PTPRZ1 55 NLGN4X-001NLDTLMTYV NLGN4X 56 VPS13B-001 SLWGGDVVL VPS13B 57 NRCAM-001 GLWHHQTEVNRCAM 58 RAD54B-001 SLYKGLLSV RAD54B 59 FABP7-001 LTFGDVVAV FABP7 60CSP-001 TMLARLASA CSPG4 61 ORMDL1-002 TLTNIIHNL ORMDL1 62 TACC3-001KLVEFDFLGA TACC3 63 DCA-001 KLGDFGLATVV DCLK2 64 PCNXL3-001 GVLENIFGVPCNXL3 65 DPYSL4-001 NLLAEIHGV DPYSL4 66 IGF2BP3-001 KIQEILTQV IGF2BP367 DROSHA-001 AVVEFLTSV DROSHA 68 ABCA13-001 ILFEINPKL ABCA13 69CCNB1-002 ILIDWLVQV CCNB1 70 CNOT1-002 SLADFMQEV CNOT1

TABLE 1d MHC class II peptides of the present invention SourceSEQ ID NO: Peptide Code Sequence Protein(s) 71 BCA-005 VKVNEAYRFRV BCANALPAYPA

TABLE 1e Additional MHC class II peptides Source SEQ ID NO: Peptide CodeSequence Protein(s) 72 BIR-002 TLGEFLKLDRERAKN BIRC5 73 PTP-010EIGWSYTGALNQKN PTPRZ1

Tables 2a and b show additional peptides according to the presentinvention, their respective SEQ ID NO, and the source proteins fromwhich these peptides may arise. All peptides in tables 2 bind to the HLAA*24 alleles.

TABLE 2a Additional peptides of the present invention SEQ ID  Peptide Source NO: Code Sequence Protein(s) 74 TMEM255A-001 YYPGVILGF TMEM255A75 ST8SIA5-001 VYYFHPQYL ST8SIA5 76 FAM120C-001 MYPYIYHVL FAM120C 77GRIK3-002 YYHFIFTTL GRIK3 78 PTP-014 YYTVRNFTL PTPRZ1 79 PTP-019NYTSLLVTW⁺⁴ PTPRZ1 80 FABP7-002 EYMKALGVGF FABP7 81 ZNF3-001 KYNDFGNSFZNF3 82 DOCK7-002 LYIYPQSLNF DOCK7 83 LOC72839-001 IFTYIHLQL LOC72839284 PJA2-001 RYQESLGNTVF PJA2 85 HEATR1-001 KYNEFSVSL HEATR1 86 GPM-002TYNYAVLKF GPM6B 87 CRB1-001 SYFENVHGF CRB1 88 PTP-016 VYDTMIEKF PTPRZ189 PTP-015 QYVFIHDTL PTPRZ1 90 PTP-018 NYTSLLVTW PTPRZ1 91 OLIG2-001IYGGHHAGF OLIG2 92 VCAN-003 TYVDSSHTI VCAN 93 SMOX-001 VYNLTQEFF SMOX 94EXOC7-001 YYQIRSSQL EXOC7 95 LZTS1-001 RYSDGLLRF LZTS1 96 FADS2-003QYQIIMTMI FADS2 97 TMEM231-001 TYIPPLLVAF TMEM231 98 ASCL1-001 EYIRALQQLASCL1 99 UNKN-003 TYIIKSVGF TXN2 100 NKA-001 QWAPILANF NKAIN1/NKAIN2/NKAIN4 101 PCD-002 RYGPQFTL PCDHG-Family 102 ARHGAP21-001 RYIPLIVDIARHGAP21 103 PNMA2-001 AYVLRLETL PNMA2 104 FADS2-002 PYNHQHEYF FADS2 105APC-001 VLPDADTLLHF APC 106 WASL-001 FYGPQVNNI WASL/ASB15 107 SLC-002KYFSFPGEL SLC1A3/SLC1A6 108 TENM4-001 AYSDGHFLF TENM4 109 ZNF749-001RYLPSSVFL ZNF749 110 EFCAB7-001 VYLTIKPLNL EFCAB7 111 DOCK7-003PYLDKFFAL DOCK7 112 BMP7-001 VYQVLQEHL BMP7 113 ITGA7-001 AFSPDSHYLLFITGA7 114 RPL-001 NYNDRYDEI RPL7A 115 HS2-001 KYNLINEYF HS2ST1 116VIM-002 NYQDTIGRL VIM 117 IFT17-001 AYLIDIKTI IFT172 118 GAB-001AYPRLSLSF GABRB1/GABRB3 119 CDCA7L-001 KFAEEFYSF CDCA7L 120 SCARA3-002YYLDKSVSI SCARA3 121 SSR1-001 NYKDLNGNVF SSR1 122 NR0B1-001 AYLKGTVLFNR0B1 123 LNX1-001 NYIDNVGNLHF LNX1 124 EP4-001 PFAKPLPTF EP400 125KIF1B-001 VYLKEANAI KIF1B 126 RHOBTB3-001 KYFGGVLEYF RHOBTB3 127KIF7-001 KYFDKVVTL KIF7 128 KIF1B-002 VYNDIGKEMLL KIF1B 129 MAPK6-001TYTSYLDKF MAPK6

The peptide according to SEQ ID NO 101 can be derived from any of thefollowing proteins: PCDHGA12, PCDHGC3, PCDHGC5, PCDHGC4, PCDHGB7,PCDHGB6, PCDHGB5, PCDHGB3, PCDHGB2, PCDHGB1, PCDHGA11, PCDHGA10,PCDHGA9, PCDHGA7, PCDHGA6, PCDHGA5, PCDHGA4, PCDHGA3, PCDHGA2, PCDHGA,PCDHGB4, or PCDHGA8. The peptide according to SEQ ID NO 109 is aframeshift of EVPSKQCVS; chr 19, 2+ frame: 57954686-57954712. W⁺⁴:Kynurenine ((S)-2-amino-4-(2-aminophenyl)-4-oxo-butanoic acid). Thepeptide according to SEQ ID NO: 99 is part of the first intron of TXN2(supported by a matching EST, BG169743.1).

TABLE 2b Additional peptides that are over- expressed in glioblastomaSEQ ID  Peptide Source  NO: Code Sequence Protein(s) 130 ASPM-002SYNPLWLRI ASPM 131 SMC4-001 HYKPTPLYF SMC4

TABLE 2cAdditional indications (e.g. cancers to be treated) based on the peptides accordingto the invention overexpressed and/or overpresented in said indicationsSEQ ID NO Sequence Peptide Code Additional Indication(s) 1 RLGIKPESVCSRP2-001 Liver, Prostate 2 ALAFKLDEV SLC10A4-001 Lung 3 YLPTFFLTVELOVL2-001 Kidney, Liver 4 GLPSGAPPG MTSS1L-001 Kidney, Liver V 8LLYDAVHIV GRIK3-001 Leukaemia 9 LLLGSPAAA SEZ6L-001 Pancreas 10 ALGDIREVANKRD40- Kidney, Colon, Rectum, Liver 001 11 SLDTLMTYV NLGN4Y-001Colon, Rectum, Prostate, Leukaemia 12 ALSVRISNV KCN-002Kidney, Liver, Pancreas 14 AVAPGPWKV MAGI2-001 Liver 18 KLFDSDPITVCLU-001 Liver TV 24 GMMTAILGV SLC35E1-002 Liver 29 YQDPHSTAV EGFR-008Kidney, Liver 30 KLTDIQIEL JAK-001 Prostate 32 RVASPTSGV IRS-001 Liver34 AMTQLLAGV TNC-001 Lung, Colon, Rectum 35 GLSEFTEYL MAP1B-002Kidney, Prostate 37 ALADIAVGV ADORA3-001Lung, Kidney, Pancreas, Prostate 40 NILEQIVSV GRI-001 Kidney 42MLFGHPLLV USP11-001 Lung, Kidney, Liver, Pancreas, Prostate SV 43RLISKFDTV EIF4E-001 Lung, Colon, Rectum, Liver, Prostate 44 LLQDRLVSVPLEKHA4- Colon, Rectum, Liver 001 45 TLLAAEFLK CCT-001 Lung, Liver QV 46LTAPPEALL NOC4-001 Lung, Kidney, Colon, Rectum, Liver, Pancreas MV 47FLDSKFYLL MAP1B-001 Kidney, Liver, Prostate 48 KLCEGFNEV CHCHD2-005Colon, Rectum, Liver 52 TLWYRAPEV CDK4-001Lung, Kidney, Stomach, Colon, Rectum, Liver 53 ILFPDIIARA MAGEF1-001Lung, Kidney, Colon, Rectum, Liver, Leukaemia 56 SLWGGDVVL VPS13B-001Lung, Colon, Rectum, Liver, Prostate 58 SLYKGLLSV RAD54B-001Lung, Kidney, Colon, Rectum, Prostate 59 LTFGDVVAV FABP7-001 Stomach 60TMLARLASA CSP-001 Kidney 61 TLTNIIHNL ORMDL1-002Lung, Kidney, Liver, Leukaemia 62 KLVEFDFLG TACC3-001Lung, Stomach, Colon, Rectum, Liver A 64 GVLENIFGV PCNXL3-001Lung, Kidney, Stomach, Colon, Rectum, Liver, Prostate 65 NLLAEIHGVDPYSL4-001 Kidney 66 KIQEILTQV IGF2BP3-001Lung, Kidney, Stomach, Colon, Rectum, Liver, Pancreas, Leukaemia 67AVVEFLTSV DROSHA-001 Lung, Kidney, Stomach, Colon, Rectum, Liver,Pancreas 68 ILFEINPKL ABCA13-001 Lung, Leukaemia 69 ILIDWLVQV CCNB1-002Lung, Kidney, Stomach, Colon, Rectum, Liver, Pancreas 70 SLADFMQEVCNOT1-002 Lung, Kidney, Colon, Rectum, Pancreas 74 YYPGVILGF TMEM255A-Lung 001 81 KYNDFGNSF ZNF3-001 Lung, Liver 82 LYIYPQSLNF DOCK7-002Lung, Kidney, Liver 83 IFTYIHLQL LOC72839- Liver 001 92 TYVDSSHTIVCAN-003 Lung, Stomach, Liver 93 VYNLTQEFF SMOX-001Lung, Kidney, Stomach 94 YYQIRSSQL EXOC7-001 Lung, Stomach, Liver 96QYQIIMTMI FADS2-003 Liver 97 TYIPPLLVAF TMEM231-Lung, Kidney, Stomach, Liver 001 103 AYVLRLETL PNMA2-001 Lung 104PYNHQHEYF FADS2-002 Lung, Liver 105 VLPDADTLL APC-001 Liver HF 108AYSDGHFLF TENM4-001 Lung, Kidney, Stomach, Prostate 109 RYLPSSVFLZNF749-001 Lung, Stomach, Liver 110 VYLTIKPLNL EFCAB7-001Lung, Stomach, Liver 112 VYQVLQEHL BMP7-001 Stomach 113 AFSPDSHYLLITGA7-001 Lung, Kidney, Liver F 115 KYNLINEYF HS2-001Lung, Kidney, Liver 116 NYQDTIGRL VIM-002 Kidney 117 AYLIDIKTI IFT17-001Lung, Kidney, Liver 118 AYPRLSLSF GAB-001 Liver 119 KFAEEFYSF CDCA7L-001Lung, Kidney, Stomach 122 AYLKGTVLF NR0B1-001 Lung 124 PFAKPLPTF EP4-001Lung, Kidney, Stomach, Liver 126 KYFGGVLEY RHOBTB3- Lung, Stomach, LiverF 001 127 KYFDKVVTLKIF7-001 Lung, Liver, Prostate 129 TYTSYLDKFMAPK6-001Lung, Liver 130 SYNPLWLRIASPM-002 Lung, Stomach, Liver 131HYKPTPLYFSMC4-001 Lung, Stomach, Liver, Prostate

Thus, another preferred aspect of the present invention relates to theuse of the peptides according to the present invention forthe—preferably combined—preferred immunotherapy of cancerous diseasesaccording to the table 2c as above in analogy to the uses as describedherein for, e.g., glioblastoma.

The peptides according to the present invention have the ability to bindto a molecule of the human major histocompatibility complex (MHC)class-I or -II.

The present invention further relates to the peptides according to thepresent invention wherein said peptides consist or consist essentiallyof an amino acid sequence according to SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71, and SEQ IDs No. 74 to 129.

The present invention further relates to the peptides according to thepresent invention, wherein said peptide is modified and/or includesnon-peptide bonds.

The present invention further relates to the peptides according to thepresent invention, wherein said peptide is part of a fusion protein, inparticular fused to the N-terminal amino acids of the HLA-DRantigen-associated invariant chain (Ii).

The present invention further relates to a nucleic acid, encoding thepeptides according to the present invention.

The present invention further relates to the nucleic acid according tothe present invention that is DNA, cDNA, PNA, RNA or combinationsthereof.

The present invention further relates to an expression vector capable ofexpressing a nucleic acid according to the present invention.

The present invention further relates to a peptide according to thepresent invention, a nucleic acid according to the present invention oran expression vector according to the present invention for use inmedicine.

The present invention further relates to antibodies according to thepresent invention.

The present invention further relates to sTCRs according to the presentinvention.

The present invention further relates to a host cell comprising anucleic acid according to the present invention or an expression vectoras described before.

The present invention further relates to the host cell according to thepresent invention that is an antigen presenting cell. The presentinvention further relates to the host cell according to the presentinvention wherein the antigen presenting cell is a dendritic cell.

The present invention further relates to a method of producing a peptideaccording to the present invention, the method comprising culturing thehost cell according to the present invention, and isolating the peptidefrom the host cell or its culture medium.

The present invention further relates to an in vitro method forproducing activated cytotoxic T lymphocytes (CTL), the method comprisingcontacting in vitro CTL with antigen loaded human class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellfor a period of time sufficient to activate said CTL in an antigenspecific manner, wherein said antigen is any peptide according to thepresent invention.

The present invention further relates to the method according to thepresent invention, wherein the antigen is loaded onto class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellby contacting a sufficient amount of the antigen with anantigen-presenting cell.

The present invention further relates to the method according to thepresent invention, wherein the antigen-presenting cell comprises anexpression vector capable of expressing said peptide containing SEQ IDNo. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 or avariant sequence thereof which is at least 90% homolog to SEQ ID No. 1to SEQ ID No. 49, SEQ ID No. 71, and SEQ IDs No. 74 to 129, or saidvariant amino acid sequence.

The present invention further relates to activated cytotoxic Tlymphocytes (CTL), produced by the method according to the presentinvention, which selectively recognize a cell which aberrantly expressesa polypeptide comprising an amino acid sequence according to the presentinvention.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence according to the present invention,the method comprising administering to the patient an effective numberof cytotoxic T lymphocytes (CTL) as according to the present invention.

The present invention further relates to the use of any peptidedescribed, a nucleic acid according to the present invention, anexpression vector according to the present invention, a cell accordingto the present invention, an antibody according to the presentinvention, or an activated cytotoxic T lymphocyte according to thepresent invention as a medicament or in the manufacture of a medicament.

The present invention further relates to a use according to the presentinvention, wherein said medicament is a vaccine. The present inventionfurther relates to a use according to the present invention, wherein themedicament is active against cancer.

The present invention further relates to particular marker proteins andbiomarkers based on the peptides according to the present invention thatcan be used in the diagnosis and/or prognosis of glioblastoma.

Further, the present invention relates to the use of these novel targetsfor cancer treatment.

Further, the present invention relates to a method for providing andproducing vaccines for patient pool with a specific set of allelesand/or patient specific.

That is, the present invention further relates to a peptide according tothe present invention according to SEQ ID No. 1 to SEQ ID No. 49, SEQ IDNo. 71, and SEQ ID No. 74 to 129, a nucleic acid according to thepresent invention or an expression vector according to the presentinvention for use in medicine.

The present invention also relates to antibodies as described hereinaccording to the present invention that are specific for a peptideaccording to a sequence selected from SEQ ID No. 1 to SEQ ID No. 49, SEQID No. 71, and SEQ ID No. 74 to 129, and methods of making these.

The present invention further relates to T-cell receptors (TCR), inparticular soluble TCR (sTCRs) targeting, in particularly specificallytargeting, a peptide according to a sequence selected from SEQ ID No. 1to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129 and/orcomplexes of said peptides according to the present invention with MHC,and methods of making these TCRs.

The present invention further relates to a host cell comprising anucleic acid according to the present invention or an expression vectoras described before. The present invention further relates to the hostcell according to the present invention that is an antigen presentingcell. The present invention further relates to the host cell accordingto the present invention wherein the antigen presenting cell is adendritic cell.

The present invention further relates to a method of producing a peptideaccording to the present invention, the method comprising culturing thehost cell according to the present invention, and isolating the peptidefrom the host cell or its culture medium.

The present invention further relates to an in vitro method forproducing activated cytotoxic T lymphocytes (CTL), the method comprisingcontacting in vitro CTL with antigen loaded human class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellfor a period of time sufficient to activate said CTL in an antigenspecific manner, wherein said antigen is any peptide according to thepresent invention.

The present invention further relates to the method according to thepresent invention, wherein the antigen is loaded onto class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellby contacting a sufficient amount of the antigen with anantigen-presenting cell. The present invention further relates to themethod according to the present invention, wherein saidantigen-presenting cell comprises an expression vector capable ofexpressing said peptide containing at least one sequence selected fromSEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129,or a variant amino acid sequence thereof.

The present invention further relates to activated cytotoxic Tlymphocytes (CTL) as described herein, produced by the method accordingto the present invention, which selectively recognize a cell whichaberrantly expresses a polypeptide comprising an amino acid sequenceaccording to the present invention.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence according to the present invention(i.e. at least one sequence selected from SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71, and SEQ ID No. 74 to 129), the method comprisingadministering to the patient an effective number of cytotoxic Tlymphocytes (CTL) as according to the present invention.

The present invention further relates to the use of any peptideaccording to the present invention, the nucleic acid according to thepresent invention, the expression vector according to the presentinvention, the host cell or cell according to the present invention, orthe activated cytotoxic T lymphocyte according to the present inventionas a medicament or in the manufacture of a medicament. The presentinvention further relates to the use according to the present invention,wherein said medicament is a vaccine.

The present invention further relates to particular marker proteins andbiomarkers based on the peptides according to the present invention thatcan be used in the diagnosis and/or prognosis of haematologicalmalignancies, in particular chronic lymphoid leukemia (CLL) cells.

Further, the present invention relates to the use of these novel targetsfor cancer treatment.

Further, the present invention relates to a method for producing apersonalized anti-cancer vaccine comprising at least one peptideaccording to the present invention, a nucleic acid according to thepresent invention, an expression vector according to the presentinvention, a host cell or cell according to the present invention, or anactivated cytotoxic T lymphocyte according to the present inventionwhich has been designed and formulated for use in an individual patient,wherein said design comprises the use of a database (“warehouse”) ofpre-selected and/or pre-screened tumour associated peptides that arepatient- and/or patient-group and/or cancer-specific.

The peptides of the present invention can be used to generate, produceand develop specific antibodies against the MHC/peptide complexes of thepresent invention (i.e. comprising at least one sequence selected fromSEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129).These antibodies can be used for therapy, targeting toxins orradioactive substances to a diseased tissue, e.g. a tumour. Another useof these antibodies can be targeting radionuclides to the diseasedtissue for imaging purposes such as PET.

Therefore, it is a further aspect of the invention to provide a methodfor producing a recombinant antibody specifically binding to a humanmajor histocompatibility complex (MHC) class I or II being complexedwith an HLA-restricted antigen (i.e. comprising at least one sequenceselected from SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ IDNo. 74 to 129), the method comprising: immunizing a geneticallyengineered non-human mammal comprising cells expressing said human majorhistocompatibility complex (MHC) class I or II with a soluble form of aMHC class I or II molecule being complexed with said HLA-restrictedantigen; isolating mRNA molecules from antibody producing cells of saidnon-human mammal; producing a phage display library displaying proteinmolecules encoded by said mRNA molecules; and isolating at least onephage from said phage display library, said at least one phagedisplaying said antibody specifically binding to said human majorhistocompatibility complex (MHC) class I or II being complexed with saidHLA-restricted antigen.

It is a further aspect of the invention to provide an antibody thatspecifically binds to a human major histocompatibility complex (MHC)class I or II being complexed with a HLA-restricted antigen, wherein theantibody preferably is a polyclonal antibody, monoclonal antibody,bispecific antibody and/or a chimeric antibody.

Yet another aspect of the present invention then relates to a method ofproducing an antibody that specifically binds to a human majorhistocompatibility complex (MHC) class I or II being complexed with anHLA-restricted antigen (i.e. comprising at at least one sequenceselected from SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ IDNo. 74 to 129), the method comprising: immunizing a geneticallyengineered non-human mammal comprising cells expressing said human majorhistocompatibility complex (MHC) class I or II with a soluble form of aMHC class I or II molecule being complexed with said HLA-restrictedantigen; isolating mRNA molecules from antibody producing cells of saidnon-human mammal; producing a phage display library displaying proteinmolecules encoded by said mRNA molecules; and isolating at least onephage from said phage display library, said at least one phagedisplaying said antibody specifically bindable to said human majorhistocompatibility complex (MHC) class I or II being complexed with saidHLA-restricted antigen. Respective methods for producing such antibodiesand single chain class I major histocompatibility complexes, as well asother tools.

It is a further aspect of the invention to provide a method forproducing a soluble T-cell receptor recognizing a specific peptide-MHCcomplex according to the invention. Such soluble T-cell receptors can begenerated from specific T-cell clones, and their affinity can beincreased by mutagenesis targeting the complementarity-determiningregions.

Stimulation of an immune response is dependent upon the presence ofantigens recognised as foreign by the host immune system. The discoveryof the existence of tumor associated antigens has raised the possibilityof using a host's immune system to intervene in tumor growth. Variousmechanisms of harnessing both the humoral and cellular arms of theimmune system are currently being explored for cancer immunotherapy.

Specific elements of the cellular immune response are capable ofspecifically recognising and destroying tumor cells. The isolation ofcytotoxic T-cells (CTL) from tumor-infiltrating cell populations or fromperipheral blood suggests that such cells play an important role innatural immune defences against cancer. CD8-positive T-cells inparticular, which recognise Class 1 molecules of the majorhistocompatibility complex (MHC)-bearing peptides of usually 8 to 10amino acid residues derived from proteins or defect ribosomal products(DRIPS) located in the cytosol, play an important role in this response.The MHC-molecules of the human are also designated as humanleukocyte-antigens (HLA).

There are two classes of MHC-molecules: MHC class I molecules that canbe found on most cells having a nucleus. MHC molecules are composed ofan alpha heavy chain and beta-2-microglobulin (MHC class I receptors) oran alpha and a beta chain (MHC class II receptors), respectively. Theirthree-dimensional conformation results in a binding groove, which isused for non-covalent interaction with peptides. MHC class I presentpeptides that result from proteolytic cleavage of predominantlyendogenous proteins, DRIPs and larger peptides. MHC class II moleculescan be found predominantly on professional antigen presenting cells(APCs), and primarily present peptides of exogenous or transmembraneproteins that are taken up by APCs during the course of endocytosis, andare subsequently processed. Complexes of peptide and MHC class Imolecules are recognized by CD8-positive cytotoxic T-lymphocytes bearingthe appropriate TCR (T-cell receptor), whereas complexes of peptide andMHC class II molecules are recognized by CD4-positive-helper-T cellsbearing the appropriate TCR. It is well known that the TCR, the peptideand the MHC are thereby present in a stoichiometric amount of 1:1:1.

CD4-positive helper T cells play an important role in inducing andsustaining effective responses by CD8-positive cytotoxic T cells (Wangand Livingstone, 2003; Sun and Bevan, 2003; Shedlock and Shen, 2003).The identification of CD4-positive T-cell epitopes derived from tumorassociated antigens (TAA) is of great importance for the development ofpharmaceutical products for triggering anti-tumor immune responses(Kobayashi et al., 2002; Qin et al., 2003; Gnjatic et al., 2003). At thetumor site, T helper cells, support a CTL friendly cytokine milieu (Qinand Blankenstein, 2000; Mortara et al., 2006) and attract effectorcells, e.g. CTLs, NK cells, macrophages, (Marzo et al., 2000; Hwang etal., 2007).

In the absence of inflammation, expression of MHC class II molecules ismainly restricted to cells of the immune system, especially professionalantigen-presenting cells (APC), e.g., monocytes, monocyte-derived cells,macrophages, dendritic cells. In cancer patients, cells of the tumorhave surprisingly been found to express MHC class II molecules (Dengjelet al., 2006).

It was shown in mammalian animal models, e.g., mice, that even in theabsence of CTL effector cells (i.e., CD8-positive T lymphocytes),CD4-positive T cells are sufficient for inhibiting manifestation oftumors via inhibition of angiogenesis by secretion of interferon-gamma(IFNγ).

Additionally, it was shown that CD4-positive T cells recognizingpeptides from tumor-associated antigens presented by HLA class IImolecules can counteract tumor progression via the induction of antibody(Ab) responses (Kennedy et al., 2003).

In contrast to tumor-associated peptides binding to HLA class Imolecules, only a small number of class II ligands of tumor associatedantigens (TAA) have been described to date.

Since the constitutive expression of HLA class II molecules is usuallylimited to cells of the immune system, the possibility of isolatingclass II peptides directly from primary tumors was not consideredpossible. However, Dengjel et al. were recently successful inidentifying a number of MHC Class II epitopes directly from tumors (WO2007/028574, EP 1 760 088 B1; (Dengjel et al., 2006).

The antigens that are recognized by the tumor specific cytotoxic Tlymphocytes, that is, their epitopes, can be molecules derived from allprotein classes, such as enzymes, receptors, transcription factors, etc.which are expressed and, as compared to unaltered cells of the sameorigin, up-regulated in cells of the respective tumor.

Since both types of response, CD8 and CD4 dependent, contribute jointlyand synergistically to the anti-tumor effect, the identification andcharacterization of tumor-associated antigens recognized by either CD8+CTLs (ligand: MHC class I molecule+peptide epitope) or by CD4-positiveT-helper cells (ligand: MHC class II molecule+peptide epitope) isimportant in the development of tumor vaccines.

The present invention also relates to a very useful MHC class II peptide(see SEQ ID NO 71). This peptide is useful against glioblastoma andother cancers over-expressing and/or over-presenting BCAN.

For a peptide to trigger (elicit) a cellular immune response, it mustbind to an MHC-molecule. This process is dependent on the allele of theMHC-molecule and specific polymorphisms of the amino acid sequence ofthe peptide. MHC-class-1-binding peptides are usually 8-12 amino acidresidues in length and usually contain two conserved residues(“anchors”) in their sequence that interact with the correspondingbinding groove of the MHC-molecule. In this way each MHC allele has a“binding motif” determining which peptides can bind specifically to thebinding groove.

In the MHC class I dependent immune reaction, peptides not only have tobe able to bind to certain MHC class I molecules being expressed bytumor cells, they also have to be recognized by T cells bearing specificT cell receptors (TCR).

The antigens that are recognized by the tumor specific cytotoxic Tlymphocytes, that is, their epitopes, can be molecules derived from allprotein classes, such as enzymes, receptors, transcription factors, etc.which are expressed and, as compared to unaltered cells of the sameorigin, up-regulated in cells of the respective tumor.

The current classification of tumor associated antigens comprises thefollowing major groups:

a) Cancer-testis antigens: The first TAAs ever identified that can berecognized by T cells belong to this class, which was originally calledcancer-testis (CT) antigens because of the expression of its members inhistologically different human tumors and, among normal tissues, only inspermatocytes/spermatogonia of testis and, occasionally, in placenta.Since the cells of testis do not express class I and II HLA molecules,these antigens cannot be recognized by T cells in normal tissues and cantherefore be considered as immunologically tumor-specific. Well-knownexamples for CT antigens are the MAGE family members or NY-ESO-1.

b) Differentiation antigens: These TAAs are shared between tumors andthe normal tissue from which the tumor arose; most are found inmelanomas and normal melanocytes. Many of these melanocytelineage-related proteins are involved in the biosynthesis of melanin andare therefore not tumor specific but nevertheless are widely used forcancer immunotherapy. Examples include, but are not limited to,tyrosinase and Melan-A/MART-1 for melanoma or PSA for prostate cancer.

c) Overexpressed TAAs: Genes encoding widely expressed TAAs have beendetected in histologically different types of tumors as well as in manynormal tissues, generally with lower expression levels. It is possiblethat many of the epitopes processed and potentially presented by normaltissues are below the threshold level for T-cell recognition, whiletheir overexpression in tumor cells can trigger an anticancer responseby breaking previously established tolerance. Prominent examples forthis class of TAAs are Her-2/neu, Survivin, Telomerase or WT1.

d) Tumor specific antigens: These unique TAAs arise from mutations ofnormal genes (such as β-catenin, CDK4, etc.). Some of these molecularchanges are associated with neoplastic transformation and/orprogression. Tumor specific antigens are generally able to induce strongimmune responses without bearing the risk for autoimmune reactionsagainst normal tissues. On the other hand, these TAAs are in most casesonly relevant to the exact tumor on which they were identified and areusually not shared between many individual tumors.

e) TAAs arising from abnormal post-translational modifications: SuchTAAs may arise from proteins which are neither specific noroverexpressed in tumors but nevertheless become tumor associated byposttranslational processes primarily active in tumors. Examples forthis class arise from altered glycosylation patterns leading to novelepitopes in tumors as for MUC1 or events like protein splicing duringdegradation which may or may not be tumor specific.

f) Oncoviral proteins: These TAAs are viral proteins that may play acritical role in the oncogenic process and, because they are foreign(not of human origin), they can evoke a T-cell response. Examples ofsuch proteins are the human papilloma type 16 virus proteins, E6 and E7,which are expressed in cervical carcinoma.

For proteins to be recognized by cytotoxic T-lymphocytes astumor-specific or -associated antigens, and to be used in a therapy,particular prerequisites must be fulfilled. The antigen should beexpressed mainly by tumor cells and not or in comparably small amountsby normal healthy tissues or in another embodiment the peptide should beover-presented by tumor cells as compared to normal healthy tissues. Itis furthermore desirable, that the respective antigen is not onlypresent in a type of tumor, but also in high concentrations (i.e. copynumbers of the respective peptide per cell). Tumor-specific andtumor-associated antigens are often derived from proteins directlyinvolved in transformation of a normal cell to a tumor cell due to afunction e.g. in cell cycle control or suppression of apoptosis.Additionally, downstream targets of the proteins directly causative fora transformation may be upregulated and thus may be indirectlytumor-associated. Such indirect tumor-associated antigens may also betargets of a vaccination approach. In both cases it is essential thatepitopes are present in the amino acid sequence of the antigen, sincesuch a peptide (“immunogenic peptide”) that is derived from a tumorassociated antigen should lead to an in vitro or in vivoT-cell-response.

Basically, any peptide able to bind a MHC molecule may function as aT-cell epitope. A prerequisite for the induction of an in vitro or invivo T-cell-response is the presence of a T cell with a correspondingTCR and the absence of immunological tolerance for this particularepitope.

Therefore, TAAs are a starting point for the development of a tumorvaccine. The methods for identifying and characterizing the TAAs arebased on the use of CTL that can be isolated from patients or healthysubjects, or they are based on the generation of differentialtranscription profiles or differential peptide expression patternsbetween tumors and normal tissues.

However, the identification of genes over-expressed in tumor tissues orhuman tumor cell lines, or selectively expressed in such tissues or celllines, does not provide precise information as to the use of theantigens being transcribed from these genes in an immune therapy. Thisis because only an individual subpopulation of epitopes of theseantigens are suitable for such an application since a T cell with acorresponding TCR has to be present and immunological tolerance for thisparticular epitope needs to be absent or minimal. In a very preferredembodiment of the invention it is therefore important to select onlythose over- or selectively presented peptides against which a functionaland/or a proliferating T cell can be found. Such a functional T cell isdefined as a T cell, which upon stimulation with a specific antigen canbe clonally expanded and is able to execute effector functions(“effector T cell”).

In case of TCRs and antibodies according to the invention theimmunogenicity of the underlying peptides is secondary. For TCRs andantibodies according to the invention the presentation is thedetermining factor.

T-helper cells play an important role in orchestrating the effectorfunction of CTLs in anti-tumor immunity. T-helper cell epitopes thattrigger a T-helper cell response of the T_(H1) type support effectorfunctions of CD8-positive killer T cells, which include cytotoxicfunctions directed against tumor cells displaying tumor-associatedpeptide/MHC complexes on their cell surfaces. In this waytumor-associated T-helper cell peptide epitopes, alone or in combinationwith other tumor-associated peptides, can serve as active pharmaceuticalingredients of vaccine compositions that stimulate anti-tumor immuneresponses.

Uses against additional cancers are disclosed in the followingdescription of the underlying polypeptides of the peptides according tothe invention.

Cysteine and Glycine-Rich Protein 2 (CSRP2)

CSRP2 is a member of the CSRP family of genes, encoding a group of LIMdomain proteins, which may be involved in regulatory processes importantfor development and cellular differentiation. CSRP2 was mapped tochromosome subband 12q21.1, a region frequently affected by deletion orbreakage events in various tumor types (Weiskirchen et al., 1997).Expression of CSRP2 is significantly elevated in moderatelydifferentiated tumor of hepatocellular carcinoma (HCC). CSRP2 is likelyto be associated with dedifferentiation of HCC (Midorikawa et al.,2002).

Solute Carrier Family 10 (Sodium/Bile Acid Cotransporter Family), Member4 (SLC10A4)

The gene SLC10A4 encodes a recently described carrier protein present inpre-synaptic terminals of cholinergic and monoaminergic neurons (Zelanoet al., 2013). SLC10A4 mRNA is ubiquitously expressed in human tissueswith the highest levels of mRNA expression in brain, placenta, andliver. In SLC10A4-transfected CHO cells, immunoblotting analysis andimmunofluorescence staining demonstrated a 49-kDa protein that isexpressed at the plasma membrane and intracellular compartments(Splinter et al., 2006). SLC10A4 may participate in vesicular storage orexocytosis of neurotransmitters or mastocyte mediators (Claro da et al.,2013).

ELOVL fatty acid elongase 2 (ELOVL2)

ELOVL2 is a member of the mammalian microsomal ELOVL fatty acid enzymefamily, which is involved in oxidative stress induction and lipidbiosynthesis and is responsible for the elongation of very long-chainfatty acids including polyunsaturated fatty acids (PUFAs) required forvarious cellular functions in mammals (Aslibekyan et al., 2012; Zadravecet al., 2011). Specifically, ELOVL2 is an essential enzyme for theformation of very-long PUFA in testis (Casado et al., 2013). A lack ofELOVL2 has been shown to be associated with a complete arrest ofspermatogenesis, with seminiferous tubules displaying only spermatogoniaand primary spermatocytes without further germinal cells (Zadravec etal., 2011). ELOVL2 shows a progressive increase in methylation thatbegins since the very first stage of life and appears to be a verypromising biomarker of aging (Garagnani et al., 2012). Its upregulationhas been reported from hepatocellular carcinoma (Zekri et al., 2012).

Metastasis Suppressor 1-Like (MTSS1L)

Radial glias play key roles in neuronal migration, axon guidance, andneurogenesis during development of the central nervous system. A recentstudy identified MTSS1L (alias ABBA) as a novel regulator of actin andplasma membrane dynamics in radial glial cells. Interestingly, ABBAlocalizes to the interface between the plasma membrane and the actincytoskeleton in radial-glia-like C6-R cells, and its depletion resultsin defects in plasma membrane dynamics and process extension(Saarikangas et al., 2008). Overexpression of GFP-tagged Abba in murinefibroblasts (NIH3T3 cells) potentiated PDGF-mediated formation ofmembrane ruffles and lamellipodia. Some data indicates that theinteraction between full-length Abba and Rac1 is implicated in membranedeformation (Zheng et al., 2010).

Protein Tyrosine Phosphatase, Receptor-Type, Z Polypeptide 1 (PTPRZ1)

PTPRZ1 (protein tyrosine phosphatase, receptor-type, Z polypeptide 1) isa member of the receptor type protein tyrosine phosphatase family andencodes a single-pass type I membrane protein with two cytoplasmictyrosine-protein phosphatase domains, an alpha-carbonic anhydrase domainand a fibronectin type-III domain. PTPRZ1 is expressed primarily in thenervous system and is synthesized by glial progenitors, and astrocytes(Canoll et al., 1993; Milev et al., 1994; Engel et al., 1996;Meyer-Puttlitz et al., 1996; Sakurai et al., 1996). PTPRZ1 isover-expressed in GBM and is thought to be involved in GBM cell motility(Muller et al., 2003; Ulbricht et al., 2003; Lu et al., 2005; Wellstein,2012). Furthermore, PTRPZ1 is frequently amplified at the genomic DNAlevel in glioblastoma (Mulholland et al., 2006). In astrocytomas, theincreased expression level of PTPRZ1 also correlates with a poorclinical prognosis (Ulbricht et al., 2003). Antagonization of PTPRZ1expression by siRNA transfection inhibits glioma growth in vitro and invivo (Ulbricht et al., 2006).

Kinesin Family Member 1A (KIF1A)

KIF1A is a monomeric motor protein of the kinesin 3 family. It isregarded as brain-specific protein, whose basic function concerns thefast anterograde axonal transport of synaptic vesicles in neurons. KIF1Ais vital for neuronal function and survival (Hirokawa and Noda, 2008).Aberrant hypermethylation of KIF1A is a frequent event in differenttypes of cancer, such as head and neck squameous cell carcinoma (Demokanet al., 2010; Kaur et al., 2010; Loyo et al., 2011; Pattani et al.,2010; Guerrero-Preston et al., 2011), lung cancer (Loyo et al., 2011),thyroid cancer and breast cancer (Brait et al., 2012; Ostrow et al.,2009). KIF1A was found as one of eight markers for minimal residualdisease (MRD) and abundantly expressed in stage IV neuroblastoma tumorsand had low to no detection in normal bone marrow/blood samples. Instage IV patients, expression levels of KIF1A in bone marrow were highlyprognostic for progression-free and overall survival (Cheung et al.,2008). Concerning minimal residual disease in neuroblastoma, KIF1A wasone of 11 genes, whose over-expression in tumor-initiating cellscorrelates with MRD (Hartomo et al., 2013).

Protocadherin Gamma Subfamily C, 5 (PCDHGC5)

Protocadherin γ-C5 (PCDHGC5) is one of the 22 members of the PCDHGfamily. The protocadherins (PCDH) are a subgroup of cadherins, which arepredominantly expressed in the central nervous system (Kallenbach etal., 2003; Hirayama and Yagi, 2006). The gamma gene cluster is organizedsimilar to an immunoglobulin cluster: 22 variable exons, which encodethe ectodomain (cadherin repeats, transmembrane and proximalintracellular domain), and 3 constant exons, which encode the commondistal moiety of the cytoplasmic domain, are joined by RNA splicing(Morishita and Yagi, 2007; Wang et al., 2002). PCDHs are involved indevelopmental tissue morphogenesis and in synapse formation andmodulation (Frank and Kemler, 2002) and the production of cerebrospinalfluid in the postnatal brain (Lobas et al., 2012). It was shown thatseveral PCDHGs, such as PCDHGC5, interact with the intracellular adaptorprotein PDCD10 (programmed cell death 10), which mediates apoptosis inneurons (Lin et al., 2010a).

Glutamate Receptor, Ionotropic, Kainate 3 (GRIK3)

Glutamate receptors are the predominant excitatory neurotransmitterreceptors in the mammalian brain and are activated in a variety ofnormal neurophysiologic processes. GRIK3 (GluR7) belongs to the kainatefamily of glutamate receptors, which are composed of four subunits andfunction as ligand-activated ion channels (Pinheiro et al., 2007).GluR5-7 subunits are expressed in human glioneuronal tumors (Aronica etal., 2001). In glioblastomas GluR7 was expressed at levels higher thanin human brain (Brocke et al., 2010). GluR7 was also found to bedifferentially expressed in several human tumor cell lines(rhabdomyosarcoma/medulloblastoma, neuroblastoma, thyroid carcinoma,lung carcinoma, astrocytoma, multiple myeloma, glioma, lung carcinoma,colon adenocarcinoma, T cell leukemia cells, breast carcinoma and colonadenocarcinoma) (Stepulak et al., 2009).

Seizure Related 6 Homolog (Mouse)-Like (SEZ6L)

The SEZ6L cDNA contains a 3,072-bp open reading frame encoding a1,024-amino acid transmembrane protein with multiple domains involved inprotein-protein interaction and signal transduction. SEZ6L wasabundantly expressed in the brain, and also expressed in a variety ofhuman tissues, including lung epithelial cells. Therefore, SEZ6L proteinis considered to be a transmembrane protein functioning as anintracellular signal transducer via protein-protein interactions in avariety of human cells (Nishioka et al., 2000). Genetic variants in theSEZ6L gene are associated with bipolar disorder I in female patients (Xuet al., 2013). A polymorphic variant of SEZ6L might be linked with anincreased risk of lung cancer (Raji et al., 2010; Gorlov et al., 2007).Methylation status of SEZ6L might also be a marker of gastric carcinoma(Kang et al., 2008). A study conducted by Suzuki at al. (2002) suggeststhat SEZ6L gene may also influence development and progression ofcolorectal cancer. The authors found that SEZ6L was one of the few geneshighly hypermethylated in primary colorectal tumors (Suzuki et al.,2002).

Ankyrin Repeat Domain 40 (ANKRD40)

ANKRD40 is a member of the ankyrin repeat protein family. ANKRD40 islocalized on chromosome 17q21.33. The function of ANKRD40 is unknown.However the ankyrin repeat is a 33-residue motif in proteins consistingof two alpha helices separated by loops, first discovered in signalingproteins in yeast Cdc10 and Drosophila Notch (Breeden and Nasmyth,1987). Domains consisting of ankyrin repeats mediate protein-proteininteractions and are among the most common structural motifs in knownproteins (Mosavi et al., 2004) Ankyrin-repeat proteins have beenassociated with a number of human diseases. These proteins include thecell cycle inhibitor p16, which is associated with cancer, and the Notchprotein (a key component of cell signalling pathways) which can causethe neurological disorder CADASIL when the repeat domain is disrupted bymutations. (Mosavi et al., 2004)

Neuroligin 4, Y-linked (NLGN4Y)

Neuroligins, such as NLGN4Y, are cell adhesion molecules present at thepostsynaptic side of the synapse and may be essential for the formationof functional synapses (Jamain et al., 2003). Skaletsky et al. (2003)determined that NLGN4Y, the Y-chromosomal homolog of NLGN4, wasexpressed in fetal and adult brain, prostate, and testis (Skaletsky etal., 2003). Some data suggested that sequence variants in NLGN4Y mightbe associated with autism or mental retardation (Ylisaukko-oja et al.,2005; Yan et al., 2008).

Potassium Inwardly-Rectifying Channel, Subfamily J, Member 10 (KCNJ10)

KCNJ10 encodes one of 16 inward rectifier-type potassium (Kir) channelsubunits, which are grouped in 7 subfamilies by homology. KCNJ10 is themajor pore forming subunit in glial cells and most data suggesthomomeric channels. Mutations in KCNJ10 have been associated withseizure susceptibility of common idiopathic generalized epilepsysyndromes (Olsen and Sontheimer, 2008). In normal brain, KCNJ10 wasdetected by IHC around microvessels, in the glia limitans/pia, and inoccasional neurons (Saadoun et al., 2003). In various human brain tumors(low- and high-grade astrocytomas and oligodendrogliomas), KCNJ10 ismislocalized as compared to healthy tissue, which may impair thebuffering capacity of glial cells and thereby to water influx, leadingto water influx (cytotoxic edema) (Warth et al., 2005). KCNJ10 was alsoupregulated in astrocytes in damaged brain (carcinoma,oligodendroglioma, and glioblastoma cells). It was hypothesized thatthis is a response to the up-regulation of Aquaporin 4 (Saadoun et al.,2003). KCNJ10 may be used as a new biomarker and as therapeutic targetwith astrocytoma (Tan et al., 2008).

Brevican (BCAN)

Brevican (BCAN) is a brain-specific member of the lectican family ofchondroitin sulfate proteoglycans. Two BCAN isoforms have been reported:a full-length isoform that is secreted into the extracellular matrix anda shorter isoform with a sequence that predicts aglycophosphatidylinositol (GPI) anchor (Gary et al., 2000). BCAN showsdramatic upregulation in gliomas, where an approximately seven-foldincrease in expression over normal levels can be detected (Gary et al.,2000; Gary et al., 1998). BCAN has also been validated as upregulated inthe biologically more aggressive grade II oligodendrogliomas (Rostomilyet al., 2010). Furthermore, BCAN has been described as selectivelyover-expressed in a type of GBM cancer stem cells which show the highestpluripotency and tumorigenicity in vivo (Gunther et al., 2008).Clinically, BCAN upregulation correlates with poor survival of patientswith high-grade gliomas (Liang et al., 2005).

Membrane Associated Guanylate Kinase, WW and PDZ Domain Containing 2(MAGI2)

MAGI2 has been localized to chromosome 7q21, a region that is deleted inuterine leiomyomas, prostate cancer and glioblastoma (Cui et al., 1998;Cunningham et al., 1996; Ishwad et al., 1995; Kim et al., 1995). MAGI2is brain-specific (Shoji et al., 2000; Wood et al., 1998; Yamada et al.,2003) and has been shown to interact with NMDA receptors at excitatorysynapses (Hirao et al., 1998). MAGI2 is involved in recruitment ofneurotransmitter receptors such as AMPA- and NMDA-type glutamatereceptors (Koide et al., 2012). MAGI2 interacts with several differentligands in brain, including PTEN (Deng et al., 2006). Binding of thetumor suppressor PTEN to the PDZ-2 domain from MAGI2 increased PTENprotein stability (Valiente et al., 2005). MAGI2 overexpression enhancesthe sensitivity of cancer cells harboring ectopic PTEN to STS-inducedapoptosis (Li et al., 2013b). Significant associations of MAGI2 with therisk for developing Alzheimer's disease have been found (Kohannim etal., 2012).

Scavenger Receptor Class A, Member 3 (SCARA3)

Using predicted exonic sequences from a cosmid mapping to chromosome8p21, Han et al. (1998) screened a human fetal brain library andisolated a novel macrophage scavenger receptor-like gene, SCARA3, whichthey called CSR1 (Han et al., 1998). CSR1 is located at 8p21-22, a locusthat is frequently deleted in several human malignancies, includingprostate cancer, head and neck squamous cell carcinoma and lung cancer(Coon et al., 2004; Gallucci et al., 2006; Kurimoto et al., 2001). HighSCARA3 levels in primary ovarian carcinomas and its up-regulation alongdisease progression from diagnosis to recurrence, suggested a role inovarian cancer biology (Bock et al., 2012). One study suggested thatCSR1 (SCARA3) protects cells from mutational damage of oxidative-freeradicals by increasing their metabolism (Han et al., 1998). Furthermore,CSR1, a newly characterized tumor-suppressor gene, undergoeshypermethylation in over 30% of prostate cancers and induce cell deaththrough a novel mechanism by hijacking a critical RNA processing enzyme(Zhu et al., 2009).

Glutamate Receptor, Ionotropic, AMPA 4 (GRIA4)

GRIA4 (also called GLUR4) belongs to a family of AMPA(alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitiveglutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). TheGluR4 subunit (GRIA4) may play a pivotal role in regulating channelproperties as well as trafficking of AMPA receptors in the adult humanbrain (Kawahara et al., 2004). Emerging evidence supports a role forglutamate in the biology of cancer. Knockdown of GLUR4 influenced theexpression and function of genes involved in invasion and metastasis,tumor suppressor genes, oncogenes and adhesion genes (Luksch et al.,2011). GRIA4 has crucial roles in growth of glioblastoma. Blockage ofCa(2+)-permeable receptors containing GRIA4 subunits may be a usefultherapeutic strategy for the prevention of glioblastoma invasion(Ishiuchi et al., 2002). Glioblastoma cells express Ca(2+)-permeableAMPARs assembled from the GluR1 and/or GluR4 subunits. Theoverexpression of Ca(2+)-permeable AMPA receptors facilitated migrationand proliferation of the tumor cells (Ishiuchi, 2009).

Clusterin (CLU)

Clusterin is an enigmatic heterodimeric glycoprotein with a nearlyubiquitous tissue distribution. It plays important roles in variouspathophysiological processes, including tissue remodeling, reproduction,lipid transport, complement regulation and apoptosis (Li et al., 2010;Niu et al., 2012). The product of the CLU gene promotes or inhibitstumorigenesis in a context-dependent manner. It has been hypothesizedthat different CLU isoforms have different and even opposing biologicalfunctions (Chaiwatanasirikul and Sala, 2011). The pro-apoptotic CLUappears to be a nuclear isoform (nuclear clusterin; nCLU), and thesecretory CLU (sCLU) is thought to be anti-apoptotic (Kim et al.,2012b). As a pleiotropic molecular chaperone, Clusterin confers survivaland proliferative advantage to cancer cells (Shiota et al., 2012) and asa membrane-stabilizing protein it appears to be involved in limiting theautophagic lysis of epithelial cells during apoptosis (Bruchovsky etal., 1996). Overexpression of sCLU was detected in primary gastriccancer (Bi et al., 2010), ovarian cancer (Yang et al., 2009), breastcancer (Niu et al., 2012), lung cancer (Panico et al., 2013),hepatocellular carcinoma (Chen et al., 2012a) and was associated withpoor survival and metastasis.

Ceramide Synthase 1 (CERS1)

Ceramide, a bioactive sphingolipid, is now at the forefront of cancerresearch. Classically, ceramide is thought to induce death, growthinhibition, and senescence in cancer cells (Saddoughi and Ogretmen,2013). Ceramide synthase 1 (CerS1) acylates sphinganine(dihydrosphingosine) to form dihydroceramide and sphingosine to formceramide (Futerman and Riezman, 2005). Jiang et al. (1998) analyzed thehuman tissue expression of CerS1 by Northern blotting and found thehighest expression in brain, skeletal muscle and testis (Jiang et al.,1998). C(18)-pyridinium ceramide treatment or endogenous C(18)-ceramidegeneration by CerS1 expression mediates autophagic cell death,independent of apoptosis in human cancer cells (Sentelle et al., 2012).Several lines of evidence point to a role for CerS1 in regulating thesensitivity to cancer chemotherapeutic agents and radiation (Min et al.,2007; Separovic et al., 2012). Further experiments demonstrated agrowth-inhibiting and pro-apoptotic effect of overexpression of CerS1and production of C18:0-ceramide in HNSCC cells (Senkal et al., 2007).

G Protein-Coupled Receptor 98 (GPR98)

G protein-coupled receptors (GPCRs) are the largest superfamily ofrelated proteins. The GPR98 gene encodes a member of the G-proteincoupled receptor superfamily. The encoded protein contains a7-transmembrane receptor domain, binds calcium and is expressed in thecentral nervous system. By linkage analysis of YAC clones, FISH, andradiation hybrid analysis, Nikkila et al. (2000) mapped the GPR98 geneto chromosome 5q14.1 (Nikkila et al., 2000). By genomic sequenceanalysis, McMillan et al. (2002) determined that the GPR98 gene contains90 exons and spans at least 600 kb (McMillan et al., 2002). Mutations inthe large GPR98 gene are associated with Usher syndrome type 2C(Ebermann et al., 2009) and familial febrile seizures (Nakayama et al.,2000). In a study, GPR98 was associated with glioblastoma multiformepatient survival (Sadeque et al., 2012).

Glycogenin 2 (GYG2)

Glycogenin is a self-glucosylating protein involved in the initiationphase of glycogen biosynthesis. It acts as a primer, by polymerizing thefirst few glucose molecules, after which other enzymes take over.Cloning of the human glycogenin-2 gene GYG2, has revealed the presenceof 11 exons and a gene of more than 46 kb in size (Zhai et al., 2000).By FISH, Mu and Roach (1998) mapped the GYG2 gene to Xp22.3. The levelof glycogenin-2 can determine glycogen accumulation and hence has thepotential to control glycogen synthesis (Mu and Roach, 1998).

Carnitine Palmitoyltransferase 1C (CPT1C)

The CPT1C gene encodes a member of the carnitine/cholineacetyltransferase family (Jogl and Tong, 2003). The encoded proteinregulates the beta-oxidation and transport of long-chain fatty acidsinto mitochondria, and may play a role in the regulation of feedingbehavior and whole-body energy homeostasis (Bonnefont et al., 2004),(Wolfgang et al., 2006). CPT1C is a newly identified and poorlyunderstood brain-specific CPT1 homologue (Reamy and Wolfgang, 2011).Recent preclinical studies suggest that a gene usually expressed only inthe brain, CPT1C, promotes cancer cell survival and tumor growth.Because of CPT1C's normally brain-restricted expression and theinability of most drugs to pass the blood-brain barrier, CPT may be anideal candidate for specific small-molecule inhibition (Reilly and Mak,2012).

Solute Carrier Family 35, Member E1 (SLC35E1)

The solute carrier family SLC35 consists of at least 17 molecularspecies in humans. The family members so far characterized encodenucleotide sugar transporters localizing at the Golgi apparatus and/orthe endoplasmic reticulum (ER) (Ishida and Kawakita, 2004). SLC35E1 wasmapped on chromosome 19p13.11 (Gerhard et al., 2004). For patients withlocally advanced rectal cancer a gene expression signature of 42 genes,which includes SLC35E1, might discriminate responders fromnon-responders. Thus, pre-therapeutic prediction of response of rectalcarcinomas to neoadjuvant chemoradiotherapy is feasible, and mayrepresent a new valuable and practical tool of therapeuticstratification (Rimkus et al., 2008).

Acid-Sensing (Proton-Gated) Ion Channel Family Member 4 (ASIC4)

ASIC4 belongs to the super-gene family of amiloride-sensitive sodiumchannels. So far five different ASICs have been cloned from mammaliantissues. ASIC4 is expressed throughout the brain, in spinal cord, andinner ear (Grunder et al., 2000). ASICs have been implicated withsynaptic transmission, pain perception as well as mechanoperception.ASIC4 shows expression throughout the central nervous system withstrongest expression in pituitary gland. ASIC4 is inactive by itself andits function is unknown. Mutations in ion channel subunits, which arehomologues of ASICs lead to neurodegeneration in Caenorhabditis elegans.It has, therefore, been speculated that similar mutations in ASICs maybe responsible for neurodegeneration in humans (Grunder et al., 2001).Furthermore, in bone ASIC4 expression was always very low abundant (Jahret al., 2005).

Collagen, Type XX, Alpha 1 (COL20A1)

COL20A1 is a collagen gene. The COL20A1 gene was mapped to thechromosome 20q13.33 (Deloukas et al., 2001). The function of this geneis still unknown. Recently, a study identified subsets of the concurrentgenes associated with breast cancer recurrence, metastases, or mortalityin survival analyses. A 16-gene signature, including COL20A1, wasestablished for disease-free survival in Han Chinese breast cancerpatients (Huang et al., 2013a).

Epidermal Growth Factor Receptor (EGFR)

EGFR is the proto-oncogene of erbB. EGFR is involved in the activationof a number of pathways that regulate the phenotype of progenitor cells.Activated EGFR tyrosine kinase activity enhances neural stem cellmigration, proliferation and survival. Overexpression of EGFR canaugment cell growth because of increased formation of activeligand:receptor complexes. Gene amplification is the mechanismunderlying overexpression of EGF receptors in GBM tumors (Thompson andGill, 1985). As EGFR signaling is also known to play a role inglioblastoma, it can be concluded that glioblastoma derives from acancer stem cell and that EGFR signals are commonly altered in theseprecursor cells (yuso-Sacido et al., 2006). A range of potentialtherapies that target EGFR or its mutant constitutively active form,AEGFR, including tyrosine kinase inhibitors (TKIs), monoclonalantibodies, vaccines, and RNA-based agents, are currently in developmentor in clinical trials for the treatment of GBM. Data from experimentalstudies evaluating these therapies have been very promising; however,their efficacy in the clinic has so far been limited by both upfront andacquired drug resistance. Many studies indicate that a multiple targetapproach will provide a more favorable future for these types oftargeted therapies in GBM (Taylor et al., 2012).

Janus Kinase and Microtubule Interacting Protein 2 (JAKMIP2)/JanusKinase and Microtubule Interacting Protein 3 (JAKMIP3)

JAKMIP2 has been identified in 2012 (Cruz-Garcia et al., 2012) as amember of the family of long α-helical coiled-coil proteins or golgins,which have diverse biological functions as motor proteins, membranetethering and vesicle transport proteins (Rose and Meier, 2004; Rose etal., 2005). JAKMIP2 is a peripheral membrane protein, which distributesacross the Golgi apparatus and post-Golgi carriers in neuroendocrinecells and may act as a negative modulator of the regulated traffickingof secretory cargo in neuroendocrine cells (Cruz-Garcia et al., 2012).JAKMIP3 was identified as a paralogue of JAKMIP2 (Cruz-Garcia et al.,2012) and a member of the family of long α-helical coiled-coil proteinsor golgins, which have diverse biological functions as motor proteins,membrane tethering and vesicle transport proteins (Rose and Meier, 2004;Rose et al., 2005). JAKMIP3 displays a long coiled-coil region highlysimilar to that of JAKMIP2 and an identical C-terminal transmembranedomain. As JAKMIP2, it is predominantly expressed in tissues containingcells with regulated secretory pathway, that is, endocrine and neuraltissues. Both are peripheral membrane proteins are located to the Golgiapparatus and post-Golgi carriers and may act as negative modulators ofthe regulated trafficking of secretory cargo in neuroendocrine cells(Cruz-Garcia et al., 2007; Cruz-Garcia et al., 2012; Malagon et al.,2009).

Wntless Homolog (Drosophila) (WLS)/Mesoderm Induction Early Response 1Homolog (Xenopus laevis) (MIER1)

WLS is a transmembrane sorting receptor, which recycles between thetrans-Golgi network and the cell surface. WLS is required for efficientsecretion of Wnt signaling proteins (Gasnereau et al., 2011). Loss ofWLS in the follicular epithelium resulted in a profound hair cyclearrest (Myung et al., 2013). WLS functions as a negative regulator ofmelanoma proliferation and spontaneous metastasis by activatingWNT/β-catenin signaling (Yang et al., 2012b). WLS is overexpressed inastrocytic glioma. Depletion of WLS in glioma and glioma-derivedstem-like cells led to decreased cell proliferation and apoptosis. WLSsilencing in glioma cells reduced cell migration and the capacity toform tumors in vivo. WLS is an essential regulator of gliomatumorigenesis (Augustin et al., 2012). MIER1 is a fibroblast growthfactor (FGF)-activated transcriptional regulator (Paterno et al., 1997).Alternatively spliced transcript variants encode multiple isoforms, someof which lack a C-terminal nuclear localization signal (Paterno et al.,2002). The oestrogen receptor-alpha (ER alpha) plays a key role inbreast development and tumorigenesis and inhibiting its activity remainsa prime strategy in the treatment of ER alpha-positive breast cancers.Differential splicing alters subcellular localization of the alpha butnot beta isoform of the MIER1 transcriptional regulator in breast cancercells (Clements et al., 2012). It was suggested that loss of nuclearMI-ER1 alpha might contribute to the development of invasive breastcarcinoma (McCarthy et al., 2008).

Insulin Receptor Substrate 2 (IRS2)

Insulin-like growth factors (IGFs) are thought to promote tumorprogression and metastasis in part by stimulating cell migration. TheIRS proteins play a central role in mediating the signals from theIR/IGF-1R that control tumor cell metabolism (Shaw, 2011). Insulinreceptor substrate-1 (IRS-1) and IRS-2 are multisite docking proteinspositioned immediately downstream from the type I IGF and insulinreceptors. IRS-2 is ubiquitously expressed and is the primary mediatorof insulin-dependent mitogenesis and regulation of glucose metabolism inmost cell types (White, 2002). IRS-2 is also ubiquitously expressed inmany types of cancer (Mardilovich et al., 2009). IRS-2 but not IRS-1 hasbeen reported to be involved in the migratory response of breast cancercells to IGFs (de Blaquiere et al., 2009). IRS-2 is often associatedwith tumor motility and invasion (Mardilovich et al., 2009). Some datashow that IRS2 is expressed in the kidney epithelium. The specificup-regulation of IRS2 in the kidney tubules of diabetic nephropathy (DN)patients indicates a novel role for IRS2 as a marker and/or mediator ofhuman DN progression (Hookham et al., 2013).

N-Acetyltransferase 8-Like (GCN5-Related, Putative) (NAT8L)

NAT8L (N-acetyltransferase 8-like) was recently identified as aspartateN-acetyltransferase, the enzyme that makes N-acetylaspartate, the secondmost abundant metabolite in mammalian brain. The NAT8L protein is aneuron-specific protein and is the N-acetylaspartate (NAA) biosyntheticenzyme, catalyzing the NAA synthesis from L-aspartate and acetyl-CoA(Wiame et al., 2010), (Ariyannur et al., 2010). NAT8L, a neuron-specificprotein, is mutated in primary NAA deficiency (hypoacetylaspartia)(Wiame et al., 2010).

Tenascin C (TNC)

Tenascin-C (TNC) is an extracellular matrix protein that is highlyup-regulated in processes that are closely associated with elevatedmigratory activity such as embryonic development (Bartsch et al., 1992),wound healing (Mackie et al., 1988) and neoplastic processes(Chiquet-Ehrismann, 1993; Chiquet-Ehrismann and Chiquet, 2003).Furthermore, TNC is over-expressed in tumor vessels that have a highproliferative index, which indicates that TNC is involved in neoplasticangiogenesis (Kim et al., 2000). In normal human brain, the expressionof TNC is detected only rarely whereas it is expressed at high levels inmalignant gliomas (Bourdon et al., 1983). Recently, TNC was identifiedas target gene of Notch signalling in malignant gliomas as well as inGBM cell lines (Sivasankaran et al., 2009). Overexpression of TNC hasfurther been reported from colon cancer (De et al., 2013), adenoidcystic carcinoma, where it has been associated with worst prognosis (Siuet al., 2012), juvenile nasopharyngeal angiofibroma, where it possiblypromotes angiogenesis (Renkonen et al., 2012), advanced melanoma(Fukunaga-Kalabis et al., 2010), pancreatic cancer, where it plays arole in proliferation, migration and metastasis (Paron et al., 2011).

Microtubule-Associated Protein 1B (MAP1B)

The MAP1B gene encodes a protein that belongs to themicrotubule-associated protein family. The proteins of this family arethought to be involved in microtubule assembly, which is an essentialstep in neurogenesis. MAP1B regulates tyrosination of alpha-tubulin inneuronal microtubules which may be important for general processesinvolved in nervous system development such as axonal guidance andneuronal migration (Utreras et al., 2008). MAP 1B was strongly anddiffusely expressed in neuroblastomas, it was also focally ormultifocally expressed in rhabdomyosarcomas and in stroma of Wilmstumors (Willoughby et al., 2008). Further, microtubule-associatedprotein 1B light chain (MAP1B-LC1) negatively regulates the activity oftumor suppressor p53 in neuroblastoma cells (Lee et al., 2008a).

Neurocan (NCAN)

Neurocan is a nervous system-specific CSPG, which belongs to theaggrecan/versican proteoglycan family. It is an important component ofthe extracellular matrix of the brain especially during development andis down-regulated in most areas of the brain during maturation (Rauch,2004; Zimmermann et al., 1994). NCAN has several binding partnersincluding the ECM components tenascin C (Grumet et al., 1994),hyaluronan (Melrose et al., 1996; Zhang et al., 2004) and the membraneproteins L1CA M (Grumet et al., 1994) and heparin sulfate proteoglycans(Akita et al., 2004). Several studies consider a correlation of NCANwith tumor invasiveness. In a comparison of locally infiltrativeglioblastoma and well-confined intracerebral metastasis of lungadenocarcinoma, NCAN showed a higher expression on mRNA and protein(IHC) level in glioblastoma (Klekner et al., 2010; Varga et al., 2010).NCAN and 3 other genes were found to correlate with the invasivephenotype of low-grade astrocytoma (Varga et al., 2012).

Adenosine A3 receptor (ADORA3)

ADORA3 encodes a protein that belongs to the family of adenosinereceptors, which are G-protein-coupled receptors that are involved in avariety of intracellular signaling pathways and physiological functions.It has been accepted that A3ARs (ADORA3) are highly expressed in tumorcells showing an important role in the development of cancer (Fishman etal., 2002), (Merighi et al., 2003), (Gessi et al., 2008), (Bar-Yehuda etal., 2008). For the human A3AR, potent and selective agonists as well asselective A3AR antagonists have been identified. CI-IB-MECA, an agonistof A3AR (ADORA3), has been reported to induce cell death in variouscancer cells. CI-IB-MECA induce a caspase-dependent cell death throughsuppression of ERK and Akt mediated by an increase in intracellularCa(2+) and ROS generation in human glioma cells (Kim et al., 2012a) andin human bladder cancer cells (Kim et al., 2010). The A3AR agonist,IB-MECA, inhibits in vivo tumor growth and metastasis of prostate cancerin mice, in addition to inhibition of in vitro cell proliferation andinvasion of prostate cancer cells (Jajoo et al., 2009).

Neuronal PAS Domain Protein 3 (NPAS3)

NPAS3 is a member of the basic helix-loop-helix PAS domain class oftranscription factors expressed in the brain, that have diverse rolesincluding cancer development and neurobehavior (Brunskill et al., 1999),(Erbel-Sieler et al., 2004), (Kamnasaran et al., 2003), (Lavedan et al.,2009). Furthermore, deletion of chromosome 14 with NPAS3 has beenreported in numerous tumors including oligodendrogliomas, melanomas, andcarcinomas of the breast, prostate gland, and urogenital tract, ascompared with normal normeoplastic tissues (Schaefer et al., 2001),(Kimchi et al., 2005), (Turashvili et al., 2007), (Harada et al., 2008).NPAS3 exhibits features of a tumor-suppressor, which drives theprogression of astrocytomas by modulating the cell cycle, proliferation,apoptosis, and cell migration/invasion and has a further influence onthe viability of endothelial cells. Of clinical importance, absence ofNPAS3 expression in glioblastomas was a significantly negativeprognostic marker of survival. While overexpressed NPAS3 in malignantglioma cell lines significantly suppressed transformation, the conversedecreased expression considerably induced more aggressive growth(Moreira et al., 2011). NPAS3 drives the progression of human malignantastrocytomas as a tumor suppressor and is a negative prognosticationmarker for survival (Moreira et al., 2011).

Neuroligin 4, X-Linked (NLGN4X)/Neuroligin 4, Y-Linked(NLGN4Y)/Neuroligin 2 (NLGN2)/Neuroligin 3 (NLGN3)

The neuroligin gene family consists of five members: NLGN1 at 3q26,NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11(Ylisaukko-oja et al., 2005).

Neuroligin 4, X-linked is a member of a cell adhesion protein familythat appears to play a role in the maturation and function of neuronalsynapses. One paper describes the detection of NLGN4X mRNA in the brainof healthy adults by RT-PCR (Jamain et al., 2003). Furthermore, anupregulation of NLGN4X has been described from human embryonic neuralstem cells and adult human olfactory bulb-derived neural stem cells(Marei et al., 2012). Mutations in the X-linked NLGN4 gene are apotential cause of autistic spectrum disorders, and mutations have beenreported in several patients with autism, Asperger syndrome, and mentalretardation (Jamain et al., 2003; Laumonnier et al., 2004; Lawson-Yuenet al., 2008). Few associations of NLGN4X with cancer have beendescribed. In gastrointestinal stromal tumors, over-expression of NLGN4Xhas been found in paediatric and young adult versus older adult cases(Prakash et al., 2005).

Neuroligins, such as NLGN4Y, are cell adhesion molecules present at thepostsynaptic side of the synapse and may be essential for the formationof functional synapses (Jamain et al., 2003). Skaletsky et al. (2003)determined that NLGN4Y, the Y-chromosomal homolog of NLGN4, wasexpressed in fetal and adult brain, prostate, and testis (Skaletsky etal., 2003). Some data suggested that sequence variants in NLGN4Y mightbe associated with autism or mental retardation (Ylisaukko-oja et al.,2005; Yan et al., 2008). NLGN2 is highly expressed in cultured neurons(Chubykin et al., 2007). Among NLGN family proteins, NLGN2 is criticalfor inhibitory synaptic transmission (Chubykin et al., 2007) and defectsin inhibitory circuit function contribute to the working memoryimpairments that represent major clinical features of schizophrenia(Lewis et al., 2005). Mutations of the neuroligin-2 gene (NLGN2) wereassociated with schizophrenia (Sun et al., 2011).

In cultured hippocampal neurons, endogenous NLGN3 was highly expressedand was localized at both glutamatergic and GABAergic synapses (Budreckand Scheiffele, 2007). Recently, point mutations in a family of neuronalcell adhesion molecules called neuroligins have been linked toautism-spectrum disorders and mental retardation. Over-expression ofwild-type NLGN3 protein in hippocampal neurons stimulates the formationof presynaptic terminals, whereas the disease-associated mutationsresult in a loss of this synaptic function (Chih et al., 2004). Further,mutations in the NLGN3 gene affect cell-adhesion molecules localized atthe synapse and suggest that a defect of synaptogenesis may predisposeto autism (Jamain et al., 2003).

Dipeptidyl-Peptidase 3 (DPP3)/Bardet-Biedl Syndrome 1 (BBS1)

The DPP3 gene encodes a protein that is a member of the S9B family inclan SC of the serine proteases. DPP3 was mapped to the chromosome11q12-q13.1 (Fukasawa et al., 2000). DPP3 is a cytosoliczinc-exopeptidase involved in the intracellular protein catabolism ofeukaryotes (Abramic et al., 2004). Tumor cytosol DPP3 activity isincreased in primary ovarian carcinomas (Simaga et al., 2003) and theproteolytic activity of DPP3 might be a biochemical indicator ofendometrial or ovarian malignancies (Simaga et al., 2008), (Simaga etal., 1998). Altered expression of DPP3 suggests involvement in primaryovarian carcinoma, oxidative stress, pain, inflammation andcataractogenesis (Prajapati and Chauhan, 2011). Bardet-Biedl syndrome(BBS) is a genetic disorder with the primary features of obesity,pigmentary retinopathy, polydactyl), renal malformations, mentalretardation, and hypogenitalism. Patients with BBS are also at increasedrisk for diabetes mellitus, hypertension, and congenital heart disease.BBS is known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2),3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6)(Mykytyn et al., 2003). The BBS1 protein may play a role in eye, limb,cardiac and reproductive system development. Mutations in this gene havebeen observed in patients with the major form (type 1) of Bardet-Biedlsyndrome (Harville et al., 2010). Experimental studies have demonstratedthat BBS1 expression is strictly limited to ciliated cells, includingphotoreceptors which are the primary ciliated cells in the retina (Azariet al., 2006).

Ubiquitin Specific Peptidase 11 (USP11)

Ubiquitination of chromosome-associated proteins is important for manyaspects of DNA repair and transcriptional regulation (Vissers et al.,2008; Weake and Workman, 2008). The full-length cDNA of USP11 was clonedfrom a Jurkat cell library. By immunofluorescence assay, USP11 primarilywas localized in the nucleus of non-dividing cells (Ideguchi et al.,2002). USP-11, a member of the ubiquitin-specific protease family, hasemerged as an essential regulator of double-strand break repair(Bayraktar et al., 2013; Wiltshire et al., 2010). USP11 mightparticipate in DNA damage repair within the BRCA2 pathway (Schoenfeld etal., 2004), but had no apparent effect on p53 (Li et al., 2002). LowUSP-11 expression correlated with better survival outcomes in women withbreast cancer (Bayraktar et al., 2013). Increased endogenous USP11 mRNAlevels in pancreatic ductal adenocarcinoma (PDA) cells were associatedwith increased sensitivity to mitoxantrone, a USP11 inhibitor.Interestingly, USP11 silencing in PDA cells also enhanced sensitivity togemcitabine (Burkhart et al., 2013).

Eukaryotic Translation Initiation Factor 4E (EIF4E)

EIF4E is a eukaryotic translation initiation factor involved indirecting ribosomes to the cap structure of mRNAs. EIF4E, an importantregulator of translation, plays a crucial role in the malignanttransformation, progression and radioresistance of many human solidtumors. The overexpression of eIF4E has been associated with tumorformation in a wide range of human malignancies (Yang et al., 2012a;Nasr et al., 2013; Wheater et al., 2010). Levels of EIF4E have also beenassociated with poor prognosis and outcome (Carroll and Borden, 2013).EIF4E regulates the translation of multiple oncogenic networks thatcontrol cell survival, proliferation, metastasis, and angiogenesis.EIF4E is a potent oncogene that promotes the nuclear export andtranslation of specific transcripts (Culjkovic-Kraljacic et al., 2012).

Pleckstrin Homology Domain Containing, Family A (PhosphoinositideBinding Specific) Member 4 (PLEKHA4)

By searching EST databases for proteins containing a putativephosphatidylinositol 3,4,5-trisphosphate-binding motif (PPBM), followedby screening a human universal cDNA library, Dowler et al. (2000)obtained a full-length cDNA encoding PLEKHA4, which they designatedPEPP1. Northern blot analysis did not detect expression in any normaltissue, but a 3-kb transcript was detected at high levels in a melanomacancer cell line. The PLEKHA4 gene was mapped to chromosome 19q13.33(Dowler et al., 2000). Pleckstrin homology domain (PH domain) is aprotein domain of approximately 120 amino acids that occurs in a widerange of proteins involved in intracellular signaling or as constituentsof the cytoskeleton (Musacchio et al., 1993). PH domains play a role inrecruiting proteins to different membranes, thus targeting them toappropriate cellular compartments or enabling them to interact withother components of the signal transduction pathways (Ingley andHemmings, 1994). The PH domain of PEPP1 is located at the N-terminalregion of PEPP1, and there are no other obvious functional motifs(Dowler et al., 2000).

Chaperonin Containing TCP1, Subunit 7 (Eta) (CCT7)

The chaperonin-containing t-complex polypeptide 1 (CCT) is a cytosolicmolecular chaperone composed of eight subunits, CCT1-CCT8, that assistsin the folding of actin, tubulin and other cytosolic proteins (Yokota etal., 2001). By FISH, Edwards et al. (1997) mapped the CCT7 gene tochromosome 2p13 (Edwards et al., 1997). Some observations suggest thatincreased expression of CCT-eta appears to be a marker for latent andactive disease in Dupuytren's contracture patients and to be essentialfor the increased contractility exhibited by the fibroblasts (Satish etal., 2013). CCT7 was shown to be different between of late stage coloncancers versus control (Nibbe et al., 2009).

Nucleolar Complex Associated 4 Homolog (S. cerevisiae) (NOC4L)

NOC4L was mapped on chromosome 12q24.33 (Milkereit et al., 2003). Thefunction of NOC4L is still unknown and the protein has not beenbiologically characterized.

Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2)

CHCHD2 was identified as a novel cell migration determinant.Intracellular localization and further functional studies suggested thatCHCHD2 and HABP1 may mutually regulate each other to balance cellmigration (Seo et al., 2010). CHCHD2 is involved in mitochondrialfunction and PKIB in protein kinase A-dependent pathway regulation(Feyeux et al., 2012). In patients with Huntington's disease CHCHD2expression differs from normal cells (Feyeux et al., 2012).

SRY (Sex Determining Region Y)-Box 8 (SOX8)/SRY (Sex Determining RegionY)-box 9 (SOX9)/SRY (Sex Determining Region Y)-box 10 (SOX10)

Sox8 is a transcription factor and belongs besides Sox9 and Sox10 togroup E of the Sox gene family. It is involved in the regulation ofembryonic development and in the determination of the cell fate. Theprotein may be involved in brain development and function. Sox8 isstrongly expressed in the embryonic and adult brain, in immature glia inthe developing cerebellum. It is also expressed in medulloblastoma andprovides an early glial marker (Cheng et al., 2001). It was shown, thatSox8 was able to form DNA-dependent heterodimers with Sox10 (Stolt etal., 2004).

Sox9 is implicated in melanogenesis in the adult and associated withcancerous transformation (Harris et al., 2010), (Flammiger et al.,2009), (Rao et al., 2010). Furthermore it was described as regulatingcartilage extracellular matrix (ECM) production and cell proliferation,and it is expressed in a wide range of cancers, where it regulates cellproliferation (Pritchett et al., 2011). Over-expression of SOX9 mRNA isclosely associated with poor clinical outcome of patients with malignantgliomas (Wang et al., 2012a). The Sox10 protein acts as anucleocytoplasmic shuttle protein and is important for neural crest andperipheral nervous system development. Sox10 was restricted to laterstages of oligodendrocyte development (Kordes et al., 2005) and it wasdescribed as an oligodendroglial lineage marker (Rousseau et al., 2006).Sox10 was consistently expressed in RIGs (Radiation-inducedglioblastomas) but rarely in pediatric GBMs (Donson et al., 2007).

Cyclin-Dependent Kinase 4 (CDK4)/Cyclin-Dependent Kinase 6 (CDK6)

CDK4 is a member of the Ser/Thr protein kinase family. It is a catalyticsubunit of the protein kinase complex that is important for cell cycleG1 phase progression. The activity of this kinase is restricted to theG1-to S phase transition during the cell cycle and its expression isprimarily controlled at the transcriptional level (Xiao et al., 2007).CDK4 and CDK6 enzymes and their regulators, e.g., cyclins, play criticalroles in embryogenesis, homeostasis, and cancerogenesis (Graf et al.,2010). In lung cancer tissues, the expression level of CDK4 protein wassignificantly increased compared to normal tissues (P<0.001). Patientswith higher CDK4 expression had a markedly shorter overall survival timethan patients with low CDK4 expression. Multivariate analysis suggestedthe level of CDK4 expression was an independent prognostic indicator(P<0.001) for the survival of patients with lung cancer. Furthermore,suppressing CDK4 expression also significantly elevated the expressionof cell cycle regulator p21 (Wu et al., 2011). In lung cells thatexpress an endogenous K-Ras oncogene, ablation of Cdk4, but not Cdk2 orCdk6, induces an immediate senescence response. No such response occursin lungs expressing a single Cdk4 allele or in other K-Ras-expressingtissues. Targeting Cdk4 alleles in advanced tumors detectable bycomputed tomography scanning also induces senescence and prevents tumorprogression (Puyol et al., 2010).

Melanoma Antigen Family F, 1 (MAGEF1)

Most known members of the MAGE (melanoma-associated antigen) superfamilyare expressed in tumors, testis and fetal tissues, which has beendescribed as a cancer/testis expression pattern (MAGE subgroup I).Peptides of MAGE subgroup I have been successfully used in peptide andDC vaccination (Nestle et al., 1998; Marchand et al., 1999; Marchand etal., 1999; Marchand et al., 1995; Thurner et al., 1999). In contrast,some MAGE genes (MAGE subgroup II), such as MAGEF1, are expressedubiquitously in all adult and fetal tissues tested and also in manytumor types including ovarian, breast, cervical, melanoma and leukemia(Nestle et al., 1998; Marchand et al., 1999; Marchand et al., 1999;Marchand et al., 1995; Thurner et al., 1999). Nevertheless,overexpression of MAGEF1 could be detected in glioblastoma (Tsai et al.,2007) and in 79% of a cohort of Taiwanese colocrectal cancer patients(Chung et al., 2010).

Neuroligin 4, X-Linked (NLGN4X)

Neuroligin 4, X-linked is a member of a cell adhesion protein familythat appears to play a role in the maturation and function of neuronalsynapses. One paper describes the detection of NLGN4X mRNA in the brainof healthy adults by RT-PCR (Jamain et al., 2003). Furthermore, anupregulation of NLGN4X has been described from human embryonic neuralstem cells and adult human olfactory bulb-derived neural stem cells(Marei et al., 2012). Mutations in the X-linked NLGN4 gene are apotential cause of autistic spectrum disorders, and mutations have beenreported in several patients with autism, Asperger syndrome, and mentalretardation (Jamain et al., 2003; Laumonnier et al., 2004; Lawson-Yuenet al., 2008). Few associations of NLGN4X with cancer have beendescribed. In gastrointestinal stromal tumors, over-expression of NLGN4Xhas been found in paediatric and young adult versus older adult cases(Prakash et al., 2005).

Vacuolar Protein Sorting 13 Homolog B (VPS13B)

VPS13B was identified as a peripheral membrane protein localized to theGolgi complex, where it overlaps with the cis-Golgi matrix proteinGM130. Consistent with its subcellular localization, VPS13B depletionusing RNAi causes fragmentation of the Golgi ribbon into ministacks(Seifert et al., 2011). Kolehmainen et al. (2003) identified the COH1gene, also known as VPS13B, within the Cohen syndrome critical region onchromosome 8q22 (Kolehmainen et al., 2003). Loss-of-function mutationsin the gene VPS13B lead to autosomal recessive Cohen syndrome (Seifertet al., 2011). Mutations of VPS13B and other genes were described ingastric and colorectal cancers with microsatellite instability (An etal., 2012).

Neuronal Cell Adhesion Molecule (NRCAM)

NRCA M (neuronal cell adhesion molecule) is a neuronal transmembranecell adhesion molecule with multiple immunoglobulin-like C2-type andfibronectin type-III domains. It is involved in the guidance, outgrowth,and fasciculation of neuronal cells (Grumet et al., 1991; Morales etal., 1993; Stoeckli and Landmesser, 1995; Perrin et al., 2001; Sakuraiet al., 2001) by forming homophilic, as well as heterophilicinteractions with other IgCAMs (Volkmer et al., 1996; Sakurai et al.,1997; Zacharias et al., 1999). NRCAM is upregulated in anaplasticastrocytomas and GBM tumor tissues as compared to normal brain, andincreased levels are correlated with the invasive behaviour (Sehgal etal., 1998). Antisense RNA against NRCAM decreases the tumorigeniccapacity of human GBM cells (Sehgal et al., 1999). NRCAM is alsooverexpressed in human papillary thyroid carcinomas at the mRNA andprotein levels (Gorka et al., 2007). Overexpression of NRCAM mRNA intumors is associated with high proliferation indices and was associatedwith a poor outcome in ependymomas (Zangen et al., 2007). In coloncancer as well, overexpression of NRCAM was associated with poorprognosis in advanced patients (Chan et al., 2011), while in prostatecancer, a high level of NRCAM expression was associated with favorabletumor phenotype and reduced risk of PSA recurrence (Tsourlakis et al.,2013).

RAD54 Homolog B (S. cerevisiae) (RAD54B)

DNA repair and recombination protein RAD54B is a protein that in humansis encoded by the RAD54B gene. RAD54 binds to double-stranded DNA, anddisplays ATPase activity in the presence of DNA. The human RAD54Bprotein is a paralog of the RAD54 protein, which plays important rolesin homologous recombination. Homologous recombination (HR) is essentialfor the accurate repair of DNA double-strand breaks (DSBs) (Sarai etal., 2008). Knockdown of RAD54B, a gene known to be somatically mutatedin cancer, causes chromosome instability (CIN) in mammalian cells(McManus et al., 2009). RAD54B elevated gene expression is significantlyassociated with shorter time-to-progression and poor OS in GBM patients(Grunda et al., 2010).

Fatty Acid Binding Protein 7, Brain (FABP7)

Fatty acid-binding proteins (FABPs) are cytosolic 14-15 kDa proteins,which are supposed to be involved in fatty acid (FA) uptake, transport,and targeting. FABP7 is highly expressed in the developing brain andretina and its expression decreases significantly in the adult CNS(Godbout et al., 1998). Based on in vitro results, it has been suggestedthat FABP7 is required for the establishment of the radial glial systemof the developing brain (Mita et al., 2007). In normal brain FABP7protein is barely detectable but shows moderate to strong nuclear andcytoplasmic expression in several GBMs. FABP7-transfected cells display5-fold greater migration than control cells. Thus, the shorter overallsurvival associated with FABP7 overexpression especially in glioblastomamay be due to increased migration and invasion of tumor cells into thesurrounding brain parenchyma (Liang et al., 2005). Further analysis ofFABP7 distribution in astrocytoma tumors indicates elevated levels ofFABP7 in infiltrating regions of the tumors proposing an important rolefor FABP7 in driving the infiltration of malignant cells into adjacentbrain tissues (Mita et al., 2007; De et al., 2012). The FABP7 promoterwas shown to be hypomethylated consistent with its overexpression in GMB(Etcheverry et al., 2010).

Chondroitin Sulfate Proteoglycan 4 (CSPG4)

CSPG4 (chondroitin sulfate proteoglycan) represents an integral membranechondroitin sulfate proteoglycan on nascent pericytes with a functionalrole in neovascularization (Ozerdem, 2006). There is accumulatingevidence from in vitro data that CSPG4 plays an important role in tumorangiogenesis. Thus, CSPG4-positive tumors have been found to havesignificantly increased neovascularization rates and vascular volumes,and CSPG4 has been shown to sequester angiostatin, which normallyinhibits endothelial cell proliferation and angiogenesis (Chekenya etal., 2002). CSPG4 is over-expressed by both tumor cells and pericytes onthe blood vessels of malignant brain tumors (Chekenya and Pilkington,2002). CSPG4 is differentially expressed in human gliomas with higherexpression in high compared to low-grade gliomas (Chekenya et al.,1999). High CSPG4 levels on tumor cells and associated vessels wereassociated with significantly shorter survival in GBM (Svendsen et al.,2011). Targeting CSPG4 in two heterogeneous GBM xenografts significantlyreduced tumor growth and oedema levels, angiogenesis and normalisedvascular function (Wang et al., 2011a). Recently, CSPG4 has even beenreported to be up-regulated in a glioblastoma-derived stem-like cellline (He et al., 2010). High expression of CSPG4 correlates withmultidrug resistance mediated by increased activation of α3β1integrin/PI3K signaling and their downstream targets, promoting cellsurvival (Chekenya et al., 2008).

ORM1-Like 1 (S. cerevisiae) (ORMDL1)

The human genes (ORMDL1, ORMDL2 and ORMDL3) are expressed ubiquitouslyin adult and fetal tissues, they encode transmembrane proteins anchoredin the endoplasmic reticulum which are likely involved in proteinfolding in the ER. By genomic sequence analysis, Hjelmqvist et al.(2002) mapped the ORMDL1 gene to chromosome 2q32.2 (Hjelmqvist et al.,2002). ORMDL proteins are the primary regulators of ceramidebiosynthesis in mammalian cells (Siow and Wattenberg, 2012). ORMDL1 isspecifically down-regulated in association with presenilin 1 (PS1)mutations (Araki et al., 2008).

Transforming, Acidic Coiled-Coil Containing Protein 3 (TACC3)

TACC3 exists in a complex with ch-TOG (colonic and hepatic tumorover-expressed gene) and clathrin that cross-links microtubules inkinetochore fibers. TACC3 is expressed in certain proliferative tissuesincluding testis, lung, spleen, bone marrow, thymus and peripheral bloodleukocytes. TACC3 expression is altered in some human tumor types. Incells, TACC3 is localized to both centrosomes and spindle microtubulesbut not at astral microtubules (Hood and Royle, 2011). TACC3 expressionwas correlated with p53 expression, and patient whose tumors highlyexpressed TACC3 and p53 had a significantly poorer prognosis thanpatients whose tumors had low-level expression for both immunostainings(P=0.006). It is suggested that increase in TACC3 may impart aproliferative advantage to glioblastoma and contribute to tumorprogression, and that TACC3 expression is a strong prognostic indicatorof clinical outcome in glioblastoma (Jung et al., 2006). Tacc3 may be anegative regulator of the Notch signaling pathway (Bargo et al., 2010).

Doublecortin-Like Kinase 2 (DCLK2)

The microtubule (MT)-associated DCX protein plays an essential role inthe development of the mammalian cerebral cortex. Identification of aprotein kinase, doublecortin kinase-2 (DCAMKL2), with a domain (DC)highly homologous to DCX was reported. Overexpression of DCAMKL2stabilizes the MT cytoskeleton against cold-induced depolymerization.Autophosphorylation of DCAMKL2 strongly reduces its affinity for MTs(Edelman et al., 2005). DCLK2 is a member of the CaMK Ser/Thr proteinkinase family, which is not calcium- or CaM-dependent, and ratherinhibits CRE-dependent gene expression (Ohmae et al., 2006). DCLK2 ishighly expressed in the central nervous system (Edelman et al., 2005) ina neuron-specific manner (Ohmae et al., 2006). It is expressed inproliferating neurons during development and persists in post-mitoticneurons in adulthood. In sympathetic neurons, DCLK2 is localized to thecell body and to the terminal segments of axons and dendrites (Tuy etal., 2008; Edelman et al., 2005).

Pecanex-Like 3 (Drosophila) (PCNXL3)

Pecanex-like protein 3 (PCNXL3) is a multi-pass membrane protein; itbelongs to the pecanex family. The PCNXL3 gene was mapped to thechromosomal region 11q12.1-q13. Three novel human tumor-associatedtranslocation breakpoints were located in the chromosome 11q13 regionbetween the markers D11S4933 and D11S546. Thus PCNXL3 might be an11q13-associated disease gene (van et al., 2000).

Dihydropyrimidinase-Like 4 (DPYSL4)

Dihydropyrimidinase-related protein 4 (DPYSL4) is a known regulator ofhippocampal neuron development. DPYSL4 is involved in growth regulation,polarization and differentiation of dental epithelial cells during toothgerm morphogenesis (Yasukawa et al., 2013). Some studies showed DPYSL4'srole in attenuating neurite outgrowth possibility through inhibitingmicrotubule polymerization, and also revealed its novel association withvimentin during nuclear condensation prior to neuronal death (Aylsworthet al., 2009). The p53 tumor suppressor gene, which is frequentlymutated in a wide variety of tumors, plays an important role inmaintaining genomic integrity. Both mRNA and protein expressions ofDPYSL4 were specifically induced by anticancer agents in p53-proficientcells. DPYSL4 is an apoptosis-inducible factor controlled by p53 inresponse to DNA damage (Kimura et al., 2011).

Insulin-Like Growth Factor 2 mRNA Binding Protein 3 (IGF2BP3)

IGF2BP3 is a member of the insulin-like growth factor-II mRNA-bindingprotein family, implicated in mRNA localization, turnover andtranslational control. The protein contains several KH (K-homologous)domains, which are important in RNA binding and are known to be involvedin RNA synthesis and metabolism. Expression occurs mainly duringembryonic development and has been described for some tumors. Thus,IGF2BP3 is considered to be an oncofoetal protein (Liao et al., 2005).IGF2BP3 may promote tumor cell proliferation by enhancing IGF-II proteinsynthesis and by inducing cell adhesion and invasion throughstabilization of CD44 mRNA (Findeis-Hosey and Xu, 2012). Moreover,IGF2BP3 expression has been studied in many human neoplasms with growingevidence that it mediates migration, invasion, cell survival and tumormetastasis (Jeng et al., 2009; Kabbarah et al., 2010; Li et al., 2011a;Liao et al., 2011; Lu et al., 2011; Hwang et al., 2012; Samanta et al.,2012) and it might also be implicated in angiogenesis (Suvasini et al.,2011; Chen et al., 2012b). In lung adenocarcinomas, a higher frequencyof IGF2BP3 expression can be detected in moderately or poorlydifferentiated adenocarcinomas, which may be associated with anaggressive biological behavior (Findeis-Hosey et al., 2010; Beljan etal., 2012; Findeis-Hosey and Xu, 2012).

Drosha, Ribonuclease Type III (DROSHA)

Drosha is a Class 2 RNase III enzyme responsible for initiating theprocessing of microRNA (miRNA), or short RNA molecules naturallyexpressed by the cell that regulate a wide variety of other genes byinteracting with the RNA-induced silencing complex (RISC) to inducecleavage of complementary messenger RNA (mRNA) as part of the RNAipathway. A microRNA molecule is synthesized as a long RNA primarytranscript known as a pri-miRNA, which is cleaved by Drosha to produce acharacteristic stem-loop structure of about 70 base pairs long, known asa pre-miRNA (Lee et al., 2003). Drosha exists as part of a proteincomplex called the Microprocessor complex, which also contains thedouble-stranded RNA binding protein Pasha (also called DGCR8) (Denli etal., 2004), which is essential for Drosha activity and is capable ofbinding single-stranded fragments of the pri-miRNA that are required forproper processing (Han et al., 2006). Human Drosha was cloned in 2000,when it was identified as a nuclear dsRNA ribonuclease involved in theprocessing of ribosomal RNA precursors (Wu et al., 2000). Drosha was thefirst human RNase III enzyme identified and cloned. The other two humanenzymes that participate in the processing and activity of miRNA are theDicer and Argonaute proteins. Both Drosha and Pasha are localized to thecell nucleus, where processing of pri-miRNA to pre-miRNA occurs. Thislatter molecule is then further processed by the RNase Dicer into maturemiRNAs in the cell cytoplasm (Lee et al., 2003). Drosha and other miRNAprocessing enzymes may be important in cancer prognosis (Slack andWeidhaas, 2008).

ATP-Binding Cassette, Sub-Family A (ABC1), Member 13 (ABCA13)

In human, the ATP-binding cassette (ABC) family of transmembranetransporters has at least 48 genes and 7 gene subfamilies. The predictedABCA13 protein consists of 5,058 amino acid residues making it thelargest ABC protein described to date (Prades et al., 2002). Knight etal. determined that ABCA13 protein is expressed in mouse and humanhippocampus and cortex, both regions relevant to schizophrenia andbipolar disorder (Knight et al., 2009). The ABCA13 gene maps tochromosome 7p12.3, a region that contains an inherited disorderaffecting the pancreas (Shwachman-Diamond syndrome) as well as a locusinvolved in T-cell tumor invasion and metastasis (INM7), and thereforeis a positional candidate for these pathologies (Prades et al., 2002).

Cyclin B1 (CCNB1)

CCNB1 is a regulatory protein involved in mitosis. The gene productcomplexes with p34(cdc2) to form the maturation-promoting factor (MPF)(Zhao et al., 2006; Gong and Ferrell, Jr., 2010). In collaboration withp53, cyclins B1 and G1 regulate the G2/M transition, a key checkpoint inthe active cell cycle (Li et al., 2003). Subsequent independentinvestigations identified in a variety of cancers a CCNB1(over-)expression which was associated with a tendency to tumorprogression and/or poor clinical prognosis e.g. in colorectal carcinoma(Li et al., 2003), RCC (Tsavachidou-Fenner et al., 2010), breast cancer(Aaltonen et al., 2009; Agarwal et al., 2009; Suzuki et al., 2007; Chaeet al., 2011), medulloblastoma (de et al., 2008), squamous cell lungcancer (Kettunen et al., 2004), gastrointestinal stromal tumors (Koon etal., 2004), esophageal squamous cell carcinoma (Song et al., 2008),laryngeal squamous cell carcinoma (Dong et al., 2002), oral tonguesquamous cell carcinoma (Harada et al., 2006), adrenocortical carcinomas(Soon et al., 2009), pulmonary adenocarcinoma (Wikman et al., 2002),non-small cell lung cancer (Cooper et al., 2009), cervical cancer (Zhaoet al., 2006), prolactin pituitary tumors (Raverot et al., 2010) andrenal cell carcinoma (Ikuerowo et al., 2006).

CCR4-NOT Transcription Complex, Subunit 1 (CNOT1)

The human CCR4-NOT deadenylase complex consists of at least nineenzymatic and non-enzymatic subunits. CNOT1 has an important role inexhibiting enzymatic activity of the CCR4-NOT complex, and thus iscritical in control of mRNA deadenylation and mRNA decay. CNOT1depletion structurally and functionally deteriorates the CCR4-NOTcomplexand induces stabilization of mRNAs, which results in the increment oftranslation causing ER stress-mediated apoptosis. Ito et al. concludethat CNOT1 contributes to cell viability by securing the activity of theCCR4-NOT deadenylase (Ito et al., 2011). siRNA-mediated depletion ofendogenous CNOT1 or other Ccr4-Not subunits in breast cancer cellsresults in deregulation of ERalpha target genes (increased induction ofERα target genes TTF1 and c-Myc). These findings define a function forthe human Ccr4-Not complex as a transcriptional repressor of nuclearreceptor signaling that is relevant for the understanding of molecularpathways involved in cancer (Winkler et al., 2006).

Baculoviral IAP Repeat-Containing 5 (Survivin) (BIRC5)

BIRC5 (Survivin) is a member of the inhibitor of apoptosis protein (IAP)family. Survivin is overexpressed in a multitude of cancer entities.Thus, in general, overexpression of survivin is thought to be associatedwith shorter overall-survival and higher malignancy grades.

Elevated levels of survivin have been reported from cancer stem cellsisolated from GBM and astrocytoma (Jin et al., 2008). It is suggestedthat survivin overexpression in brain gliomas might play an importantrole in malignant proliferation, anti-apoptosis and angiogenesis (Zhenet al., 2005; Liu et al., 2006). Several analyses were performed tostudy survivin expression and its impact on survival in glioblastoma. Tosummarize, survivin expression, especially the simultaneous expressionin nucleus and cytoplasm in astrocytic tumors was significantlyassociated with malignancy grade (with highest survivin expression inglioblastoma) and shorter overall survival times compared with patientswho had survivin-negative tumors (Kajiwara et al., 2003; Saito et al.,2007; Uematsu et al., 2005; Mellai et al., 2008; Grunda et al., 2006;Xie et al., 2006; Sasaki et al., 2002b; Chakravarti et al., 2002).Additionally, Survivin expression was significantly increased inrecurrent GBM compared with newly diagnosed tumors (Guvenc et al.,2013). As survivin is such a promising target for cancer therapy,studies using survivin-derived peptides showed that survivin isimmunogenic in tumor patients by eliciting CD8+ T cell-mediatedresponses. In addition, surviving specifically stimulated CD4+ T-cellreactivity in peripheral blood lymphocytes from the same patients(Casati et al., 2003; Piesche et al., 2007).

Transmembrane Protein 255A (TMEM255A)

The TMEM255A gene (alias FAM70A) was located on chromosome Xq24 (Ross etal., 2005). The function of TMEM255A is still unknown. But thechromosome Xq24, were TMEM255A was mapped, is also the location for somecancer/testis (CT) genes, which are expressed in some tumors (Chen etal., 2006). Furthermore, in 80% of HER2-positive breast tumors deletionat Xq24 was observed, covering both previously known genes as well asnovel genes in relation to cancer (Tina et al., 2012).

ST8 Alpha-N-Acetyl-Neuraminide Alpha-2,8-Sialyltransferase 5 (ST8SIA5)

By screening a human brain cDNA library with a DNA probe generated fromthe cDNA sequence of mouse Siat8e, followed by 5-prime RACE of mRNA fromhuman brain tissue, Kim et al. (1997) cloned human SIAT8E(alpha-2,8-sialyltransferase V, ST8SIA5). Northern blot analysisdetected expression of 11- and 2.5-kb transcripts in fetal and adultbrain (Kim et al., 1997). ST8SIA5 is a type II membrane protein that maybe present in the Golgi apparatus. The encoded protein, which is amember of glycosyltransferase family 29, may be involved in thesynthesis of gangliosides GD1c, GT1a, GQ1b, and GT3 from GD1a, GT1b,GM1b, and GD3, respectively (Kim et al., 1997). Gangliosides play animportant role in neuronal differentiation processes. The regulation ofganglioside levels is related to the induction of neuronal celldifferentiation. Some results suggest that the ST8Sia5 gene increasesganglioside GQ1b and improves neuronal differentiation via the ERK1/2MAP kinase pathway (Kwak et al., 2011).

Family with Sequence Similarity 120C (FAM120C)

Family with sequence similarity 120C is a protein in humans that isencoded by the FAM120C gene. FAM120C encodes a potential transmembraneprotein and lies in a region where mutations and deletions have beenassociated with intellectual disability and autism (Qiao et al., 2008).FAM120C seems to be expressed at low levels in several adult and fetalhuman tissues. It consists of 16 coding exons and maps to Xp11.22. The5-prime end of the FAM120C gene lies within a CpG island (Holden andRaymond, 2003).

Fatty Acid Binding Protein 7, Brain (FABP7)

Fatty acid-binding proteins (FABPs) are cytosolic 14-15 kDa proteins,which are supposed to be involved in fatty acid (FA) uptake, transport,and targeting. FABP7 is highly expressed in the developing brain andretina and its expression decreases significantly in the adult CNS(Godbout et al., 1998). Based on in vitro results, it has been suggestedthat FABP7 is required for the establishment of the radial glial systemof the developing brain (Mita et al., 2007). In normal brain FABP7protein is barely detectable but shows moderate to strong nuclear andcytoplasmic expression in several GBMs. FABP7-transfected cells display5-fold greater migration than control cells. Thus, the shorter overallsurvival associated with FABP7 overexpression especially in glioblastomamay be due to increased migration and invasion of tumor cells into thesurrounding brain parenchyma (Liang et al., 2005). Further analysis ofFABP7 distribution in astrocytoma tumors indicates elevated levels ofFABP7 in infiltrating regions of the tumors proposing an important rolefor FABP7 in driving the infiltration of malignant cells into adjacentbrain tissues (Mita et al., 2007; De et al., 2012). The FABP7 promoterwas shown to be hypomethylated consistent with its overexpression in GMB(Etcheverry et al., 2010).

Zinc Finger Protein 3 (ZNF3)

The ZNF family represents a large group of molecules which are involvedin various aspects of transcriptional regulation. The ZNF3 gene wasmapped to chromosome 7q22.1. Northern blot analysis of mRNA from celllines of various tissue origins showed ubiquitous expression of a 3.5-kbtranscript (Pannuti et al., 1988). Multiple mutations in the zinc finger(ZNF) family genes, including ZNF3, were found in HNSCC (head and necksquamous cell carcinoma) tumors (Nichols et al., 2012; Nichols et al.,2012). In HRneg/Tneg breast cancer ZNF3 was identified as an outcomepredictor regarding metastatic outcome of early stage (Yau et al.,2010).

Dedicator of Cytokinesis 7 (DOCK7)

DOCK7 (Dedicator of cytokinesis 7), also known as Zir2, is a large (˜240kDa) protein involved in intracellular signalling networks. It is amember of the DOCK-C subfamily of the DOCK family of guanine nucleotideexchange factors (GEFs) which function as activators of small Gproteins.

DOCK7 expression has been reported in neurons (Watabe-Uchida et al.,2006), (Yamauchi et al., 2008). DOCK7 functions as an essential anddownstream regulator of receptor for advanced glycation end products(RAGE)-mediated cellular migration (Yamamoto et al., 2013). DOCK7 alsofunctions as an intracellular substrate for ErbB2 to promote Schwanncell migration (Yamauchi et al., 2008). Furthermore, DOCK7 inducesmultiple axon formation when over-expressed and prevents axon formationwhen it is knocked down (Watabe-Uchida et al., 2006). DOCK7 interactionwith TACC3 controls interkinetic nuclear migration and the genesis ofneurons from radial glial progenitor cells (RGCs) during corticaldevelopment (Yang et al., 2012b).

Uncharacterized LOC728392 (LOC728392)

LOC728392 is an uncharacterized protein located on chromosome 17p13.2(Kim et al., 2006), (Zody et al., 2006). To this date, there was nofurther characterization of the protein LOC728392.

Praja Ring Finger 2, E3 Ubiquitin Protein Ligase (PJA2)

PJA2 is a widely expressed RING (Really Interesting New Gene) protein.RING-finger proteins contain cysteine-rich, zinc-binding domains and areinvolved in the formation of macromolecular scaffolds important fortranscriptional repression and ubiquitination (Sasaki et al., 2002a). Innervous tissue, PJA2 is distributed mainly on the cytoplasmic side ofthe membranes constituting endoplasmic reticulum and Golgi apparatus,but also to the postsynaptic density region of axosomatic synapses(Nakayama et al., 1995). In human GBM samples, high protein and mRNAexpression of PJA2 was detected, whereas expression in humanastrocytomas was low. This suggests that PJA2 expression correlates withmalignancy, which is based on the inhibition of the Hippo tumorsuppressor pathway by accumulated PJA2 (Lignitto et al., 2013).

HEAT Repeat Containing 1 (HEATR1)

Human HEATR1, also called UTP10, had been identified as anuncharacterized protein termed BAP28. Zebrafish embryos homozygous for amutant bap28 allele display excess apoptosis primarily in the centralnervous system (Azuma et al., 2006). Human HEATR1 (UTP10) was mapped tochromosome 1q43. Endogenous human UTP10 is clearly enriched in nuclelolias revealed by staining of HeLa cells with affinity-purified antibodiesraised against recombinant protein. It has been suggested, that UTP10binds to chromatin throughout the rDNA repeat (Prieto and McStay, 2007).

Glycoprotein M6B (GPM6B)

GPM6B belongs to a proteolipid protein family, which is expressed inneurons and in oligodendrocytes in the brain. The knowledge of thebiological function of this protein family is sparse, but theirexpression in most brain regions have led to the hypothesis that theyare involved in cellular housekeeping functions such as membranetrafficking and cell-to-cell communication (Fjorback et al., 2009).Taken together, GPM6B is thought to have a function in the developmentof the nervous system (Mobius et al., 2008). GPM6B was firstly describedas a brain specific protein expressed mainly in neurons andoligodendrocytes (Werner et al., 2001; Yan et al., 1993), but severalrecent studies demonstrate its broad distribution throughout many celltypes and tissues (Charfi et al., 2011). GPM6B expression has beendescribed in some tumor entities. For example, it is expected to be Bleukemia-specific and showed significant overexpression in these tumors(Charfi et al., 2011). In ovarian cancer, GPM6B is detectable frompatients serum and is among the most promising candidates for an earlystage marker (Urban et al., 2011).

Crumbs Homolog 1 (Drosophila) (CRB1)

The CRB1 gene encodes a protein which is similar to the Drosophilacrumbs protein and localizes to the inner segment of mammalianphotoreceptors. CRB1 mapped to 1q31-q32.1, a region harboring a geneinvolved in a severe form of autosomal recessive retinitis pigmentosa(den Hollander et al., 1999). Pellikka et al. (2002) showed that CRB1localizes to corresponding subdomains of the photoreceptor apical plasmamembrane (Pellikka et al., 2002). CRB1 may organize an intracellularprotein scaffold in the human retina (den Hollander et al., 2001).Mutations in the CRB1 gene are associated with a severe form ofretinitis pigmentosa, RP12, and with Leber congenital amaurosis;(Coppieters et al., 2010); (Walia et al., 2010); (van de Pavert et al.,2007). Jacobson et al. (2003) suggested that the CRB1 disease pathwaydisturbs the development of normal human retinal organization byinterrupting naturally occurring apoptosis (Jacobson et al., 2003).

Oligodendrocyte Lineage Transcription Factor 2 (OLIG2)

Oligodendrocyte lineage transcription factor 2 (OLIG2) is a member ofthe OLIG family of basic helix-loop-helix transcription factors. Itplays a key role in the cell fate specification of oligodendrocytes andmotor neurons in the dorsal spinal cord during development (Lu et al.,2000), (Takebayashi et al., 2000). OLIG2 is a universal marker ofdiffuse gliomas (oligodendroglioma, astrocytoma, glioblastoma, and mixedglioma) (Lu et al., 2001), (Marie et al., 2001). Olig2 is strictlyrequired to maintain the malignancy of oligodendroglioma cells, sinceits silencing by interfering RNA abrogates tumor propagation (Appolloniet al., 2012). It has been proposed that OLIG2 transcript level maycorrelate with malignant progression of astrocytoma (Bozinov et al.,2008). Furthermore, OLIG2-positive glioma-initiating cells were proposedas therapeutic target (Fu et al., 2013). Recent studies have identifiedstem cells in brain cancer. In this study they observe expression of theCNS-restricted transcription factor, OLIG2, in human glioma stem andprogenitor cells reminiscent of type C transit-amplifying cells ingerminal zones of the adult brain. These findings identify anOlig2-regulated lineage-restricted pathway critical for proliferation ofnormal and tumorigenic CNS stem cells (Ligon et al., 2007).

Versican (VCAN)

VCAN gene is a member of the aggrecan/versican proteoglycan family. Theprotein encoded is a large chondroitin sulfate proteoglycan and is amajor component of the extracellular matrix. This protein is involved incell adhesion, proliferation, migration and angiogenesis and plays acentral role in tissue morphogenesis and maintenance.

VCAN is expressed in a variety of tissues. It is highly expressed in theearly stages of tissue development, and its expression decreases aftertissue maturation. Its expression is also elevated during wound repairand tumor growth. In the adult human brain, VCAN is expressed mainly inthe white matter of the frontal lobe, cerebellum, brainstem, and spinalcord, in close association with astrocytes and oligodendrocytes (Ghoshet al., 2010). VCAN has been found in many malignancies includingmelanomas and prostate and in multiple human cancers its isoforms hasbeen shown a differential expression (Ghosh et al., 2010; Zheng et al.,2004). A higher VCAN expression in tumor tissue than in the surroundingnormal tissues was observed analysing three high-grade human braintumors (Zheng et al., 2004).

Spermine Oxidase (SMOX)

SMOX is an inducible FAD-dependent polyamine oxidase, which oxidizesspermine, to produce spermidine, H₂O₂, and 3-aminopropanal (Wang et al.,2001). SMOX is located on chromosome 20p13 and encodes for severalsplice variants (Murray-Stewart et al., 2002). SMOX is a highlyinducible enzyme, its deregulation can alter polyamine homeostasis, anddysregulation of polyamine catabolism is often associated with severaldisease states. SMOX participates in drug response, apoptosis, responseto stressful stimuli and etiology of several pathological conditions,including cancer (Cervelli et al., 2012). Elevated cellular polyaminelevels are a common feature of cancer cells, including GBM cells, andthe polyamine pathway has been explored as a potential therapeutictarget to inhibit polyamine biosynthesis or activate polyaminecatabolism inhibitor (Jiang et al., 2007).

Exocyst Complex Component 7 (EXOC7)

EXOC7 is a component of the exocyst, which is an evolutionarilyconserved octameric protein complex essential for exocytosis (Kee etal., 1997). The exocyst targets secretory vesicles at specific domainsof the plasma membrane for cell surface expansion and protein secretion(Zuo et al., 2006). By analysis of a human-rodent hybrid panel, Kikunoet al. (1999) mapped the EXOC7 gene to chromosome 17q25 (Kikuno et al.,1999). The exocyst is involved in vesicle trafficking, specifically thetethering and spatial targeting of post-Golgi vesicles to the plasmamembrane prior to vesicle fusion. It is implicated in a number of cellprocesses, including exocytosis and also cell migration and growth (Zuoet al., 2006). The exocyst plays important roles in cell invasion bymediating the secretion of MMPs at focal degrading sites and regulatingactin dynamic (Liu et al., 2009). A set of 14 genes, including EXOC7,might be an outcome predictor in early stage hormone receptor-negativeand triple-negative breast cancer (Yau et al., 2010).

Leucine Zipper, Putative Tumor Suppressor 1 (LZTS1)

The FEZ1/LZTS1 gene was identified as a candidate tumor suppressor geneat 8p22 by Ishii et al in 1999 (Ishii et al., 1999). LZTS1 has beenshown to regulate growth of human tumor cell lines and physicallyinteracts with cell-cycle regulators in that context (Cabeza-Arvelaiz etal., 2001); (Ishii et al., 2001); (Vecchione et al., 2002). Introductionof LZTS1 into LZTS1-negative cancer cells resulted in suppression oftumorigenicity and reduced cell growth with accumulation of cells at thelate S-G2/M stage of the cell cycle (Ishii et al., 2001). The FEZ1/LZTS1(FEZ1) gene is frequently altered in human cancer, including prostate(Hawkins et al., 2002), lung (Lin et al., 2013), bladder (Abraham etal., 2007) and breast (Chen et al., 2009) cancer. Frequent reduction inexpression and infrequent mutations were reported. Hypermethylation of aCpG island in the LZTS1 promoter appeared to be frequent and could beresponsible for the reduced expression of LZTS1 in cancer cells (Toyookaet al., 2002), (Vecchione et al., 2001).

Fatty Acid Desaturase 2 (FADS2)

Fatty acid desaturase 2 (FADS2) also known as delta(6) fatty aciddesaturase (D6D) is an enzyme that in humans is encoded by the FADS2gene. Fatty acid desaturase 2 is a member of the fatty acid desaturase(FADS) gene family. Marquardt et al. (2000) identified the FADS2 gene onchromosome 11q12-q13.1 (Marquardt et al., 2000). FADS2 is therate-limiting enzyme in mammalian synthesis of long-chainpolyunsaturated fatty acids (Nwankwo et al., 2003). FADS2 function lossat the cancer hotspot 11q13 locus diverts lipid signaling precursorsynthesis to unusual eicosanoid fatty acids (Park et al., 2011). FADS2is upregulated in hepatocellular carcinoma (Muir et al., 2013). FADS2may be involved in the pathogenesis of breast cancer (Pender-Cudlip etal., 2013) and the expression of delta-6-desaturase is associated withaggressiveness of breast cancer (Lane et al., 2003). Furthermore,inhibiting delta-6 desaturase activity suppresses tumor growth in mice(He et al., 2012).

Transmembrane Protein 231 (TMEM231)

TMEM231 encodes a transmembrane protein, which is a component of the B9complex involved in the formation of the diffusion barrier between thecilia and plasma membrane. TMEM231 localizes to the basal body beforeand independently of intraflagellar transport in a Septin 2(Sept2)-regulated fashion (Chih et al., 2012). Mutations in TMEM231cause several ciliopathies. These are multiorgan system disorders causedby dysfunction of the primary cilium, a cytoskeletal appendage whichplays essential roles in cellular homeostasis and organ development(Nigg and Raff, 2009; Hildebrandt et al., 2011). Very recently, compoundheterozygosity for two mutations in TMEM231 was identified in threepatients with Joubert syndrome, a predominantly autosomal recessivedisorder characterised by a distinctive midhindbrain malformation,oculomotor apraxia, breathing abnormalities and developmental delay.JBTS is genetically heterogeneous, involving genes required forformation and function of non-motile cilia (Parisi and Glass, 1993;Srour et al., 2012).

Achaete-Scute Complex Homolog 1 (Drosophila) (ASCL1)

Achaete-scute homolog-1 ASCL1 (also termed hASH1 in humans) is a basichelix-loop-helix transcription factor important in early development ofneural and neuroendocrine (NE) progenitor cells in multiple tissuesincluding the CNS, autonomic nervous system, adrenal medulla, thyroid,lung, and prostate, among others (Guillemot et al., 1993; Borges et al.,1997; Fode et al., 2000; Ball, 2004; Nakada et al., 2004; Pattyn et al.,2006; Miki et al., 2012; Righi et al., 2012). As it is crucial for earlydevelopment of the sympathetic nervous system, it is transientlyexpressed in sympathetic neuroblasts during embryogenesis (Soderholm etal., 1999). Furthermore, ASCL1 is expressed in immature olfactoryneurons and is required for their development (Carney et al., 1995).ASCL1 is essential for the maintenance and in vivo tumorigenicity of GBMCSCs (Rheinbay et al., 2013). An efficient generation of inducedneuronal (iN) cells from glioma cells could be achieved by the infectionwith three transcription factors: Ascl1, Brn2 and Ngn2 (ABN). Thiscauses glioma cell death, decreased tumor growth and conversion of humanglioma cells to functional neurons (Zhao et al., 2012b). ASCL1upregulation in progressive astrocytoma is accompanied by inhibition ofNotch signaling (Somasundaram et al., 2005). ASCL1 is expressed in amajority of primary neuroblastomas and neuroblastoma cell lines(Axelson, 2004). During neuroblastoma differentiation, the ASCL1-pathwayis responsible for the up-regulation of IGF2 (Li et al., 2011b).

Na+/K+ Transporting ATPase Interacting 1 (NKAIN1)/Na+/K+ TransportingATPase Interacting 2 (NKAIN2)/Na+/K+ Transporting ATPase Interacting 4(NKAIN4)

NKAIN proteins 1-4 are a family of evolutionary conserved transmembraneproteins that localize to neurons and interact with the Na,K-ATPase β1subunit. There are three splice variants of NKAIN2, 3 and 4, whereasonly a single form of NKAIN1 was found. All four family members arehighly expressed in mouse brain with distinct and overlapping expressionin different brain regions. Interestingly, a short splice variant ofNKAIN4 is brain- and testis-specific, whereas a longer splice variant ofNKAIN4 is expressed ubiquitously (Gorokhova et al., 2007). The genomicregion NKAIN1-SERINC2 harbors SNPs, which are causally associated withalcohol dependence in Europeans (Zuo et al., 2013). Disruption of theNKAIN2 gene has been implicated in neurological disorders, e.g. in achild with developmental delay and recurrent infections (Bocciardi etal., 2005; Yue et al., 2006). In addition, SNPs in NKAIN2 have beenassociated with neuroticism (Calboli et al., 2010) and alcoholdependence (Wang et al., 2011b). Human NKAIN2 was identified first asgene, which is disrupted within the breakpoint region 6q21-22 in theT-cell lymphoma/leukemia cell lines HT-1 and ATN-1 (Tagawa et al.,2002). It may also be a candidate tumor suppressor gene in prostatecancer, although no functional experimental data are available for thatidea (Mao et al., 2011).

Protocadherin Gamma Family (PCDHG-Family)

The protocadherins (PCDH) are a subgroup of cadherins, which arepredominantly expressed in the central nervous system (Kallenbach etal., 2003; Hirayama and Yagi, 2006). The gamma gene cluster (PCDHG-)includes 22 genes divided into 3 subfamilies. The gamma gene cluster isorganized similar to an immunoglobulin cluster: 22 variable exons, whichencode the ectodomain (cadherin repeats, transmembrane and proximalintracellular domain), and 3 constant exons, which encode the commondistal moiety of the cytoplasmic domain, are joined by RNA splicing(Morishita and Yagi, 2007; Wang et al., 2002). PCDHs are involved indevelopmental tissue morphogenesis and in synapse formation andmodulation (Frank and Kemler, 2002) and the production of cerebrospinalfluid in the postnatal brain (Lobas et al., 2012). It was shown thatseveral PCDHGs interact with the intracellular adaptor protein PDCD10(programmed cell death 10), which mediates apoptosis in neurons (Lin etal., 2010a). Agglomerative epigenetic aberrations—for example of theprotocadherin gene family clusters on chromosome 5 (PCDHA, PCDHB, andPCDHG)—are a common event in human breast cancer (Novak et al., 2008).

Rho GTPase Activating Protein 21 (ARHGAP21)

ARHGAP21 functions preferentially as a GTPase-activating protein (GAP)for CDC42 and regulates the ARP2/3 complex and F-actin dynamics at theGolgi through control of CDC42 activity (Dubois et al., 2005). SeveralRho GTPase-activating proteins (RhoGAPs) are implicated in tumorprogression through their effects on Rho GTPase activity. ARHGAP21 is aRhoGAP with increased expression in head and neck squamous cellcarcinoma and with a possible role in glioblastoma tumor progression(Lazarini et al., 2013). ARHGAP21 modulate cell migration through thecontrol of Cdc42 and FAK activities (Bigarella et al., 2012). ARHGAP21is expressed in the nuclear and perinuclear regions of severalglioblastoma derived cell lines. ARHGAP21 might act as a tumorsuppressor gene and might be a master regulator of migration having acrucial role in controlling the progression of different tumor types(Bigarella et al., 2009).

Paraneoplastic Ma Antigen 2 (PNMA2)

Human PNMA2 encodes the paraneoplastic antigen Ma2 which belongs to thehuman PNMA family (Schuller et al., 2005). In healthy persons, PNMA2expression is restricted to neuronal tissue. In the CNS, neuronal cellsshow discrete subnuclear and cytoplasmic immunostaining (Gultekin etal., 2000; Voltz et al., 1999). In cancer tissue, PNMA2 expression hasbeen shown for testicular cancer (Voltz et al., 1999; Leja et al.,2009), breast cancer (Sahashi et al., 2003), lung cancer (Barnett etal., 2001), small intestine neuroendocrine tumors and liver metastasis(Leja et al., 2009). PNMA2 was identified as novel marker gene forneuroendocrine carcinoma cells (Leja et al., 2009). Patients withPNMA2-positive tumors may develop anti-PNMA2 antibodies, which induceneurological degenerative syndromes, such as paraneoplastic encephalitis(PNE) (Sahashi et al., 2003). As the neurological symptoms of PNEstrongly affect the patient's condition and may be fatal (Barnett etal., 2001), cancer treatment should be forced in such patients (Kraker,2009).

Adenomatous Polyposis Coli (APC)

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5(DP2.5) is a protein that in humans is encoded by the APC gene. The APCprotein plays a critical role in several cellular processes thatdetermine whether a cell may develop into a tumor. The APC protein helpscontrol how often a cell divides, how it attaches to other cells withina tissue, or whether a cell moves within or away from a tissue. APC is akey tumor suppressor gene that acts as a gatekeeper of intestinalepithelial homeostasis by restraining cytoplasmic cellular levels ofβ-catenin, the central activator of transcription in the Wnt signalingpathway (Minde et al., 2011). Mutations in the human APC gene are linkedto familial adenomatous polyposis and to the progression of sporadiccolorectal and gastric tumors (Rubinfeld et al., 1993). APC gene is alsoa candidate susceptibility gene for attenuated polypotic syndromes (Zhouet al., 2001). The association between brain tumors and multiplecolorectal adenomas can result from two distinct types of germ-linedefects: mutation of the APC gene or mutation of a mismatch-repair gene(Hamilton et al., 1995).

Wiskott-Aldrich Syndrome-Like (WASL)

Neural Wiskott-Aldrich syndrome protein is a protein that in humans isencoded by the WASL gene. The Wiskott-Aldrich syndrome (WAS) family ofproteins share similar domain structure, and are involved intransduction of signals from receptors on the cell surface to the actincytoskeleton (Kovacs et al., 2011). WASL associates with Cdc42, known toregulate formation of actin filaments, and the cytoskeletal organizingcomplex Arp2/3 and is ubiquitously expressed and shows highestexpression in neural tissues (Kovacs et al., 2011). WASL and the arp2/3complex are critical regulators of actin in the development of dendriticspines and synapses (Wegner et al., 2008). The Arp2/3 complex with theassociated protein WASL mediates multigeneration dendritic protrusionsfor efficient 3-dimensional cancer cell migration (Giri et al., 2013).WASL is involved in the metastasis of human breast cancer(Escudero-Esparza et al., 2012) and in primary brain tumors (Khalil andEl-Sibai, 2012).

Solute Carrier Family 1 (Glial High Affinity Glutamate Transporter),Member 3 (SLC1A3)/Solute Carrier Family 1 (High AffinityAspartate/Glutamate Transporter), Member 6 (SLC1A6)

SLC1A3 encodes a member of a member of a high affinity glutamatetransporter family. SLC1A3 is also often called the GLutamate ASpartateTransporter (GLAST) or Excitatory Amino Acid Transporter 1 (EAAT1).GLAST is predominantly expressed in the plasma membrane, allowing it toremove glutamate from the extracellular space (Langley et al., 2009).Various acute and chronic brain diseases result in disturbed expressionof the glial glutamate transporters, GLAST/EAAT-1 and GLT-1/EAAT-2, andsubsequent secondary neuronal cell death (Unger et al., 2012). Theexpression of glutamate transporters (GLT-1 and GLAST) in astrocytes andmicroglia are differentially regulated following nerve injury (Xin etal., 2009). Autoantigen specific T cells inhibit glutamate uptake inastrocytes by decreasing expression of astrocytic glutamate transporterGLAST (Korn et al., 2005). SLC1A3 might be associated with glioma cellmotility (Tatenhorst et al., 2004). Inhibition of glutamate transporterenhances the therapeutic efficacy of doxorubicin (Sugiyama et al.,2001).

The glutamate transporter gene SLC1A6 encodes the glutamate transporterEAAT4. It is thought, that at least one susceptibility locus forschizophrenia may be located within or nearby SLC1A6 in the Japanesepopulation (Deng et al., 2007). Furthermore, it is localized neuronal inthe mammalian central nervous system (Jackson et al., 2001) andexpressed predominantly in the cerebellum (Need et al., 2009).

Teneurin Transmembrane Protein 4 (TENM4)

Teneurin-4 (Ten-4/Odz4) is a type II transmembrane protein that ishighly expressed in the CNS. Ten-4 is also expressed in developing eyesand somites, as well as in tail bud and limbs (Tucker andChiquet-Ehrismann, 2006); (Kenzelmann-Broz et al., 2010). Ten-4expression is induced in response to endoplasmic reticulum (ER) stress(Wang et al., 1998), and an involvement of Ten-4 has been suggested inmouse gastrulation (Lossie et al., 2005) and bipolar disorder in humans(2011). However, the biological function of Ten-4 remains unknown. Somefindings suggest that teneurin-4 is a novel regulator of oligodendrocytedifferentiation and that it plays a critical role in the myelination ofsmall-diameter axons in the CNS (Suzuki et al., 2012).

Zinc Finger Protein 749 (ZNF749)

ZNF749 was mapped on chromosome 19q13.43 (Grimwood et al., 2004),(Tsuritani et al., 2007). This gene has 4 transcripts (splice variants).To date, the ZNF749 has not been characterized and the function of thisgene is unknown.

EF-Hand Calcium Binding Domain 7 (EFCAB7)

EFCAB7 was mapped on chromosome 1p31.3 (Mehrle et al., 2006), (Wiemannet al., 2004). EFCAB7 is an uncharacterized protein with unknownbiological function.

Bone Morphogenetic Protein 7 (BMP7)

BMP7/OP-1 belongs together with other BMPs to the transforming growthfactor (TGF) 0 family. BMP7 is a very pleiotropic growth factor. Bonemorphogenic proteins (BMPs) play a key role in bone formation. In recentyears, recombinant BMPs, particularly BMP2 and BMP7/OP-1, have been usedtherapeutically in patients with large bone defects or delayed orimpaired fracture healing, with the notion that locally applied BMPwould promote bone repair (Geesink et al., 1999), (Donati et al., 2008),(Zimmermann et al., 2006), (Garrison et al., 2010). BMP-7 belongs to thesuperfamily of transforming growth factor β-like cytokines, which canact either as tumor suppressors or as tumor promoters depending on celltype and differentiation. BMP7 expression have been reported to beinvolved in the growth of several cancer cells, such as osteosarcoma,malignant melanoma, prostate cancer, breast cancer, renal cell cancer,colorectal cancer, and gastric cancer, causing increased aggression orsuppression (Motoyama et al., 2008), (Kwak et al., 2007), (Sulzbacher etal., 2002), (Rothhammer et al., 2007), (Masuda et al., 2004), (Alarmo etal., 2006). Endogenous neural precursor cells protect the young brainfrom glioblastoma by releasing BMP7, which acts as a paracrine tumorsuppressor that represses proliferation, self-renewal andtumor-initiation of stem-like glioblastoma cells (Chirasani et al.,2010).

Integrin, Alpha 7 (ITGA7)

Integrins are heterodimeric proteins, which mediate interactions betweencells and ECM or other cells. ITGA7 encodes the integrin alpha 7, whichforms a heterodimer with the integrin beta 1 chain (Vignier et al.,1999). The beta 1 chain interacts with the cytoskeletal componentα-actinin, thus ensuring signaling between the cytoskeleton and thebasal lamina (Otey et al., 1990). ITGA7 is mainly and abundantlyexpressed in skeletal and cardiac muscle (Pegoraro et al., 2002; Leunget al., 1998). In human, mutation, deletion or reduced expression ofITGA7 is strongly correlated with muscular dystrophy and myopathy(Pegoraro et al., 2002; Hayashi et al., 1998). ITGA7 was associated withmalignant transformation in melanoma (Kramer et al., 1991b; Kramer etal., 1991a; Kramer et al., 1989). In line with this, enhanced ITGA7expression in squamous cell carcinoma of the tongue suggested ITGA7 as apotential marker of metastases (Carinci et al., 2005). Some resultssuggest that blocking of ITGA7 may be an important step duringcarcinogenesis. However, the authors noted that the role of ITGA7 intumor growth remains unclear and may depend on the cell type involved(Ren et al., 2007).

Ribosomal Protein L7a (RPL7A)

Cytoplasmic ribosomes, organelles that catalyze protein synthesis,consist of a small 40S subunit and a large 60S subunit. The RPL7A geneencodes a ribosomal protein that is a component of the 60S subunit. Manyribosomal proteins, particularly those of the large subunit, includingribosomal protein L7a (RPL7a), are composed of a globularsurface-exposed RNA-binding domain that binds to the rRNA core tostabilize its structure. Although the critical activities of decodingand peptide transfer are rRNA-based, ribosomal proteins also play animportant role in the process of protein synthesis (Wool, 1996). RPL7aplays a critical role in stabilizing ribosomes by binding to rRNA (De etal., 1993; Huxley and Fried, 1990). In addition to its function in theribosome, RPL7a may also be involved in cell growth and differentiationby interacting with human thyroid hormone receptor (THR) and retinoicacid receptor (RAR) and in turn inhibiting the activities of the twonuclear hormone receptors (Burris et al., 1995). In osteosarcoma, RPL7amRNA and protein expression was significantly down-regulated comparedwith samples from normal bone and benign bone lesion tissues and lowRPL7A mRNA expression was a significant poor prognostic indicator foroverall survival in patients with high grade lesion developed lungmetastasis at the time of diagnosis of the primary osteosarcoma (Zhenget al., 2009). On the other hand, RPL7a is reported to be up-regulatedin colorectal cancer (Wang et al., 2000). An over-expression of RPL7amRNA was also confirmed in prostate-cancer tissue samples by in situhybridization (Vaarala et al., 1998). Furthermore, ribosomal proteinsL7a might be associated with malignant brain tumor formation (Kroes etal., 2000).

Heparan Sulfate 2-O-Sulfotransferase 1 (HS2ST1)

Heparan sulfate 2-O-sulfotransferase 1 is an enzyme that in humans isencoded by the HS2ST1 gene. Heparan sulfate biosynthetic enzymes are keycomponents in generating a myriad of distinct heparan sulfate finestructures that carry out multiple biologic activities. HS2ST1 transfersulfate to the 2 position of the iduronic acid residue of heparansulfate. The disruption of the HS2ST1 gene resulted in no kidneyformation in knockout embryonic mice, indicating that the absence ofthis enzyme may interfere with the signaling required for kidneyformation (Seki et al., 1997). HS2ST1 is involved in prostate cancercell proliferation, invasion, and growth factor signalling (Ferguson andDatta, 2011). Increased gene expression of HS2ST1 in malignant comparedto normal plasma cells was associated with a good prognosis (Bret etal., 2009).

Vimentin (VIM)

Vimentin, a major constituent of the intermediate filament (IF) familyof proteins, is ubiquitously expressed in normal mesenchymal cells andis known to maintain cellular integrity and provide resistance againststress (Schietke et al., 2006). In recent years, vimentin has beenrecognized as a marker for epithelial-mesenchymal transition (EMT)(Thomson et al., 2005). Various reports show that vimentin plays animportant role in cell migration (Eckes et al., 1998), (Eckes et al.,2000), (Kang and Massague, 2004). Vimentin has also been indicated inregulation of cell survival, cell adhesion and lipid transport (Sarriaet al., 1992), (McInroy and Maatta, 2007), (Mendez et al., 2010).Increased vimentin expression has been reported in various tumor celllines and tissues including prostate cancer, breast cancer, endometrialcancer, CNS tumors, malignant melanoma and gastrointestinal tumorsincluding pancreatic, colorectal and hepatic cancers. Vimentin'soverexpression in cancer correlates well with accelerated tumor growth,invasion, and poor prognosis.

Vimentin has been used as a molecular marker for GBM and astrocytomas(Shiras et al., 2003), (Yang et al., 1994). Further, a novelcell-penetrating peptide derived from the intermediate filament proteinvimentin, called Vim-TBS.58-81 has recently been described. The authorsshow that it enters cells from a glioblastoma line via endocytosis whereit distributes throughout the cytoplasm and nucleus (Balzeau et al.,2012).

Intraflagellar Transport 172 Homolog (Chlamydomonas) (IFT172)

IFT172, also known as Selective Lim-domain Binding protein (SLB), is acomponent of the Intraflagellar Transport (IFT) complex. Mutations thataffect components of the IFT machinery are known to compromise theformation and function of cilia. Cilia play essential roles in thedifferentiation and survival of olfactory and retinal neurons andauditory hair cells (Scholey and Anderson, 2006). IFT172, a complex Bsubunit, plays an essential role in the flagellar entry of IFT-dynein(Williamson et al., 2012). Further, IFT172 is potentially required forearly regulation of FGF8 at the midbrain-hindbrain boundary andmaintenance of the isthmic organizer (Gorivodsky et al., 2009).

Gamma-Aminobutyric Acid (GABA) A Receptor, Beta 1(GABRB1)/Gamma-Aminobutyric Acid (GABA) A Receptor, Beta 3 (GABRB3)

Gamma-aminobutyric acid receptor subunit beta-1 is a protein that inhumans is encoded by the GABRB1 gene. The gamma-aminobutyric acid (GABA)A receptor is a multisubunit chloride channel that mediates the fastestinhibitory synaptic transmission in the central nervous system. Thisgene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome4p12 in a cluster of genes encoding alpha 4, alpha 2 and gamma 1subunits of the GABA A receptor. Alteration of this gene is implicatedin the pathogenetics of schizophrenia (Vasquez et al., 2013).Gamma-aminobutyric acid receptor subunit beta-3 is a protein that inhumans is encoded by the GABRB3 gene. This gene is located on the longarm of chromosome 15 in a cluster with two genes encoding relatedsubunits of the family. Mutations in this gene may be associated withthe pathogenesis of Angelman syndrome, Prader-Willi syndrome, and autism(Nurmi et al., 2003).

Cell Division Cycle Associated 7-Like (CDCA7L)

Cell division cycle-associated 7-like protein is a protein that inhumans is encoded by the CDCA7L gene (Ou et al., 2006). CDCA7L showsnuclear colocalization with c-Myc, and interacts with c-Myc both invitro and in mammalian cells (Huang et al., 2005). CDCA7L inhibited theMAOA promoter and MAOA enzymatic activity and acted as a repressor inapoptotic signaling pathways (Ou et al., 2006). CDCA7L is a Mycinteractor associated with metastatic medulloblastoma (Zhou et al.,2010).

Signal Sequence Receptor, Alpha (SSR1)

Translocon-associated protein subunit alpha is a protein that in humansis encoded by the SSR1 gene. The signal sequence receptor (SSR) is aglycosylated endoplasmic reticulum (ER) membrane receptor associatedwith protein translocation across the ER membrane. The SSR consists of 2subunits, a 34-kD glycoprotein encoded by this gene and a 22-kDglycoprotein (Hirama et al., 1999). SSR1 was detected in 50% ofmedulloblastomas and in 78% of primitive neuroectodermal tumors (Johnsonet al., 2013).

Nuclear Receptor Subfamily 0, Group B, Member 1 (NR0B1)

NR0B 1 (also called dosage-sensitive sex reversal/adrenal hypoplasiacongenital critical region on the X chromosome 1; DAX1) acts as anegative regulator of steroid production, and is expressed in thereproductive and endocrine systems (Niakan and McCabe, 2005). NR0B1 ishighly expressed in several kinds of cancers, such as endometrialcarcinoma (Saito et al., 2005), ovarian carcinoma (Abd-Elaziz et al.,2003), prostatic carcinoma (Nakamura et al., 2009), and Ewing's sarcoma(Mendiola et al., 2006; Camoes et al., 2012; Kinsey et al., 2006). Inlung adenocarcinoma, higher levels of NR0B 1 expression correlated withhigher rates of lymph node metastasis and recurrence (Oda et al., 2009).

Ligand of Numb-Protein X 1, E3 Ubiquitin Protein Ligase (LNX1)

E3 ubiquitin-protein ligase LNX is an enzyme that in humans is encodedby the LNX1 gene. Studies have approved that LNX1 could participate insignal transduction, such as Notch pathway, and play an important rolein tumorigenesis. Some results suggested that down-regulation of LNX1could result in cell cycle arrest in G0/G1 phase through inhibition ofβ-catenin, MAPK, NFκB, c-Myc-dependent pathway and activation of p53,TGF-β-dependent pathway (Zheng et al., 2011). Gene sequence alterationsand amplifications of LNX1 are present in a subset of human gliomas(Blom et al., 2008; Holtkamp et al., 2007). Human LNX1 was downregulatedin gliomas including low- and high-grade ones (Chen et al., 2005).

E1A Binding Protein p400 (EP400)

E1A-binding protein p400 is a protein that in humans is encoded by theEP400 gene. p400 is a mediator of E1A-induced downregulation ofepidermal growth factor receptor and of apoptosis (Flinterman et al.,2007; Samuelson et al., 2005). Mutations in the EP400 Gene weredescribed for near haploid lymphoblastic leukemia patients (Chen et al.,2013a). Further, a genome-wide siRNA screen identified EP400 as aregulator of human papillomavirus oncogene expression (Smith et al.,2010). The p400/Tip60 ratio is critical for colon cancer cellsproliferation and response to therapeutic drugs through the control ofstress-response pathways (Mattera et al., 2009).

Kinesin Family Member 1B (KIF1B)

The KIF1B gene on 1p36, a region commonly deleted in neural crestcancers, was found to be a proapoptotic factor for sympatheticprecursors. KIF1B beta mutations were detected in pheochromocytomas andneuroblastomas, two sympathetic lineage tumors, suggesting a role forthis gene in cancer (Yeh et al., 2008). The KIF1B-related pathway mightbe involved in the pathogenesis of hepatitis B virus-relatedhepatocellular carcinoma (Casper et al., 2011). KIF1B is down-regulatedin high stage neuroblastomas (Caren et al., 2005; Ohira et al., 2000;Nagai et al., 2000). Cell surface localization of MT1-MMP is dependenton KIF1B, which consequently plays a critical role in gastric cancerinvasion (Dong et al., 2013). KIF1B is associated withpheochromocytomas, a neuroendocrine tumor (Galan and Kann, 2013).

Rho-Related BTB Domain Containing 3 (RHOBTB3)

Rho-related BTB domain-containing protein 3 is a protein that in humansis encoded by the RHOBTB3 gene. RHOBTB3 is a member of theevolutionarily conserved RhoBTB subfamily of Rho GTPases (Rivero et al.,2001; Boureux et al., 2007). RHOBTB genes are upregulated in some cancercell lines, suggesting that these proteins might participate intumorigenesis (Ramos et al., 2002). Berthold et al. (2008) alsodescribed a potential role of the RhoBTB subfamily in tumorigenesis(Berthold et al., 2008b). A decreased expression of RHOBTB and CUL3genes in kidney and breast tumor samples was observed (Berthold et al.,2008a).

Kinesin Family Member 7 (KIF7)

The KIF7 gene encodes a cilia-associated protein belonging to thekinesin family. This protein plays a role in the sonic hedgehog (SHH)signaling pathway through the regulation of GLI transcription factors(Li et al., 2012b). It functions as a negative regulator of the SHHpathway by preventing inappropriate activation of GLI2 in the absence ofligand, and as a positive regulator by preventing the processing of GLI3into its repressor form. KIF7 is implicated in a variety of diseasesincluding Joubert, hydrolethalus and acrocallosal syndromes. It is alsoinvolved in primary cilium formation and the Hedgehog signalling pathwayand may play a role in cancer (Klejnot and Kozielski, 2012). Aberrantactivation of Hedgehog signaling pathway leads to pathologicalconsequences in a variety of human tumors, such as gastric cancer andpancreatic cancer. KIF7 is implicated in the Hedgehog signaling (Katohand Katoh, 2005).

Mitogen-Activated Protein Kinase 6 (MAPK6)

Mitogen-activated protein kinase 6 (MAPK6, also called ERK3) is anenzyme that in humans is encoded by the MAPK6 gene. MAPK6 is a member ofthe Ser/Thr protein kinase family, and is most closely related tomitogen-activated protein kinases (MAP kinases). There is an increase inERK3 transcripts in oral cancer tissue compared to healthy tissue;colorectal cancer tissues had higher ERK3 expression levels thatadjacent normal mucosa. Elevated ERK3 protein levels are also associatedwith gastric cancer. Increased ERK3 transcripts or protein levels havealso been observed in breast cancer, melanoma and non-small cancer lungcells (Kostenko et al., 2012). Certain observations suggest that ERK3may play some roles in tumor suppression, including its apparentnegative regulatory effect on cell cycle progression, cellproliferation, and migration (Cargnello and Roux, 2011).

Asp (Abnormal Spindle) Homolog, Microcephaly Associated (Drosophila)(ASPM)

Abnormal spindle-like microcephaly associated (ASPM) is the humanorthologue of the Drosophila abnormal spindle (asp). ASPM have beenimplicated in spindle organization, spindle orientation, mitoticprogression, and cytokinesis (Van et al., 2009); (Higgins et al., 2010).ASPM overexpression, like many Wnt-activating components, is associatedwith increased cell proliferation and tumor development, supporting acommon effect on proliferation (Lin et al., 2008); (Bikeye et al.,2010); (Vulcani-Freitas et al., 2011). As overexpression of ASPM wasobserved in several tumor cells lines and reduction of ASPM levelsinhibited cellular proliferation, most publications suggest ASPM asnovel target in cancer therapy. In glioblastoma multiforme, ASPM ishighly overexpressed as compared to normal brain and other body tissues(Horvath et al., 2006). Several studies have found that ASPM expressionlevels have a strong positive correlation with the malignant phenotypeand WHO grade of glioma, as ASPM was overexpressed in GBM as compared toastrocytomas and expression increased at recurrence (Bikeye et al.,2010; Bikeye et al., 2011; Hagemann et al., 2008; Marie et al., 2008).It was suggested that ASPM is involved in the malignant progression ofglioma and represents an attractive therapeutic target. ASPM expressionnegatively correlates with clinical outcome in GBM (Horvath et al.,2006; Visnyei et al., 2011).

Structural Maintenance of Chromosomes 4 (SMC4)

Structural maintenance of chromosomes (SMC) proteins are chromosomalATPases, highly conserved from bacteria to humans, that play fundamentalroles in many aspects of higher-order chromosome organization anddynamics (Losada and Hirano, 2005). The SMC4 protein is a core componentof the condensin complex that plays a role in chromatin condensation andhas also been associated with nucleolar segregation, DNA repair, andmaintenance of the chromatin scaffold (Cervantes et al., 2006). SMC2 andSMC4 function as the core of the condensin complexes that are essentialfor chromosome assembly and segregation (Losada and Hirano, 2005).RT-PCR studies on human cancer samples show that the RNA is expressedhighly in many cancer cell lines and cancer specimens, including humanbreast cancers, prostate cancers, colon cancers, and pancreatic cancers(Egland et al., 2006).

Thioredoxin 2 (TXN2)

TXN2 encodes a mitochondrial member of the thioredoxin family, a groupof small multifunctional redox-active proteins. The encoded protein mayplay important roles in the regulation of the mitochondrial membranepotential and in protection against oxidant-induced apoptosis (Tanaka etal., 2002). TXN and TXN2 regulate the proliferation and survival ofadipose tissue-derived mesenchymal stem cells, and these processes aremediated by the activation of ERK1/2 (Song et al., 2011). Because of itsrole in stimulating cancer cell growth and as an inhibitor of apoptosis,thioredoxin offers a target for the development of drugs to treat andprevent cancer. The protein TXN2 is linked to breast cancer (Seibold etal., 2011) and therefore the peptide SEQ ID No 99 is also useful in thisindication.

The protein CSRP2 is linked to hepatocellular carcinoma (Midorikawa etal., 2002) and therefore the peptide SEQ ID No 1 is also useful in thisindication.

The protein ELOVL2 is linked to hepatocellular carcinoma (Zekri et al.,2012) and therefore the peptide SEQ ID No 3 is also useful in thisindication.

The protein KIF1A is linked to head and neck squameous cell carcinoma(Demokan et al., 2010; Kaur et al., 2010; Loyo et al., 2011; Pattani etal., 2010; Guerrero-Preston et al., 2011), neuroblastoma (Hartomo etal., 2013), lung cancer (Loyo et al., 2011), thyroid cancer and breastcancer (Brait et al., 2012; Ostrow et al., 2009) and therefore thepeptide SEQ ID No 6 is also useful in these indications.

The protein GRIK3 is linked to rhabdomyosarcoma/medulloblastoma,neuroblastoma, thyroid carcinoma, lung cancer, astrocytoma, multiplemyeloma, T cell leukemia cells, breast cancer and colon adenocarcinoma(Stepulak et al., 2009) and therefore the peptide SEQ ID No 8 is alsouseful in these indications.

The protein SEZ6L is linked to lung cancer (Raji et al., 2010; Gorlov etal., 2007), gastric carcinoma (Kang et al., 2008), colorectal cancer(Suzuki et al., 2002) and therefore the peptide SEQ ID No 9 is alsouseful in these indications.

The protein KCNJ10 is linked to astrocytoma (Tan et al., 2008) andtherefore the peptide SEQ ID No 12 is also useful in this indication.

The protein SCARA3 is linked to ovarian cancer (Bock et al., 2012),prostate cancer (Zhu et al., 2009) and therefore the peptide SEQ ID No16 is also useful in this indication.

The protein CLU is linked to primary gastric cancer (Bi et al., 2010),ovarian cancer (Yang et al., 2009), breast cancer (Niu et al., 2012),lung cancer (Panico et al., 2013), hepatocellular carcinoma (Chen etal., 2012a), colorectal cancer (Rodriguez-Pineiro et al., 2012),prostate cancer (Ammar and Closset, 2008), pancreatic cancer (Jin etal., 2012) and therefore the peptide SEQ ID No 18 is also useful inthese indications.

The protein CERS1 is linked to head-and-neck squamous cell carcinoma(Senkal et al., 2007) and therefore the peptide SEQ ID No 19 is alsouseful in this indication.

The protein SLC35E1 is linked to rectal carcinoma (Rimkus et al., 2008)and therefore the peptide SEQ ID No 24 is also useful in thisindication.

The protein COL20A1 is linked to breast cancer (Huang et al., 2013b) andtherefore the peptide SEQ ID No 28 is also useful in this indication.

The protein EGFR is linked to renal cell carcinoma (Lee et al., 2008b),prostate cancer (Wang et al., 2013), lung cancer (Bivona et al., 2011),melanoma (Girotti et al., 2013), head and neck squamous cell carcinoma(Deng et al., 2013), breast cancer (Li et al., 2009), colon cancer(Yokoi et al., 2005), and therefore the peptide SEQ ID No 29 is alsouseful in these indications.

The protein WLS is linked to melanoma (Yang et al., 2012b) and theprotein MIER1 is linked to breast cancer (McCarthy et al., 2008) andtherefore the peptide SEQ ID No 31 is also useful in these indications.

The protein IRS2 is linked to breast cancer (Clark et al., 2011),prostate cancer (Heni et al., 2012), gastric cancer (Zhao et al.,2012a), ovarian cancer (Meunier et al., 2010), endometrial cancer (Caganet al., 2010) and therefore the peptide SEQ ID No 32 is also useful inthese indications.

The protein TNC is linked to colon cancer (De et al., 2013), adenoidcystic carcinoma (Siu et al., 2012), juvenile nasopharyngealangiofibroma (Renkonen et al., 2012), advanced melanoma(Fukunaga-Kalabis et al., 2010), pancreatic cancer (Paron et al., 2011)and therefore the peptide SEQ ID No 34 is also useful in theseindications.

The protein MAP1B is linked to neuroblastoma (Willoughby et al., 2008)and therefore the peptides SEQ ID No 35 and No 47 is also useful in thisindication.

The protein ADORA3 is linked to prostate cancer (Jajoo et al., 2009),hepatocellular carcinoma (Bar-Yehuda et al., 2008), primary thyroidcancer (Morello et al., 2008), colon carcinoma (Gessi et al., 2004),bladder cancer (Kim et al., 2010) and therefore the peptide SEQ ID No 37is also useful in this indication.

The protein NLGN4X is linked to gastrointestinal stromal tumor (Prakashet al., 2005) and therefore the peptide SEQ ID No 39 is also useful inthis indication.

The protein DPP3 is linked to primary ovarian carcinoma (Simaga et al.,2003) and therefore the peptide SEQ ID No 41 is also useful in thisindication.

The protein USP11 is linked to breast cancer (Bayraktar et al., 2013),pancreatic ductal adenocarcinoma (Burkhart et al., 2013) and thereforethe peptide SEQ ID No 42 is also useful in this indication.

The protein EIF4E is linked to breast cancer (Zindy et al., 2011),cervical cancer (Wang et al., 2013), nasopharyngeal carcinoma (Wu etal., 2013), gastric cardiac adenocarcinoma (Yang et al., 2013), livercancer (Wang et al., 2012b), laryngeal carcinoma (Yi et al., 2012),pancreatic cancer (Martineau et al., 2013), melanoma (Populo et al.,2012), NSCLC (Li et al., 2012a), head and neck squamous cell carcinoma(Sunavala-Dossabhoy et al., 2011), liver cancer (Choi et al., 2011),prostate cancer (Hay, 2010; Furic et al., 2010), endometrial cancer(Choi et al., 2011) and therefore the peptide SEQ ID No 43 is alsouseful in these indications.

The protein CCT7 is linked to colon cancer (Nibbe et al., 2009) andtherefore the peptide SEQ ID No 45 is also useful in this indication.

The protein SOX9 is linked to metastatic melanoma (Rao et al., 2010) andthe protein SOX10 is linked to melanoma (Mohamed et al., 2012), salivarygland cancer (Ohtomo et al., 2013), breast carcinoma (Cimino-Mathews etal., 2013), and therefore the peptide SEQ ID No 49 is also useful inthese indications.

The protein CDK4 is linked to lung cancer (Puyol et al., 2010), oralsquamous cell carcinoma (Poomsawat et al., 2010), hepatocellularcarcinoma (Chen et al., 2013b), breast cancer (Harrison Pitner andSaavedra, 2013) and therefore the peptide SEQ ID No 52 is also useful inthis indication.

The protein CDK6 is linked to oral squamous cell carcinoma (Poomsawat etal., 2010), hepatocellular carcinoma (Chen et al., 2013b) and thereforethe peptide SEQ ID No 52 is also useful in this indication.

The protein MAGEF1 is linked to lung cancer (Tsai et al., 2007),colocrectal cancer patients (Chung et al., 2010) and therefore thepeptide SEQ ID No 53 is also useful in these indications.

The protein NLGN4X is linked to gastrointestinal stromal cancer (Prakashet al., 2005) and therefore the peptide SEQ ID No 55 is also useful inthis indication.

The protein VPS13B is linked to gastric and colorectal cancer (An etal., 2012) and therefore the peptide SEQ ID No 56 is also useful in thisindication.

The protein NRCAM is linked to papillary thyroid carcinoma (Gorka etal., 2007), colon cancer (Chan et al., 2011), prostate cancer(Tsourlakis et al., 2013) and therefore the peptide SEQ ID No 57 is alsouseful in these indications.

The protein RAD54B is linked to esophageal squamous cell carcinoma (Liet al., 2013a) and therefore the peptide SEQ ID No 58 is also useful inthis indication.

The protein FABP7 is linked to renal cell carcinoma (Teratani et al.,2007), melanoma (Goto et al., 2006), breast cancer (Liu et al., 2012a)and therefore the peptides SEQ ID No 59 and No 80 are also useful inthese indications.

The protein TACC3 is linked to lung cancer (Jung et al., 2006) andtherefore the peptide SEQ ID No 62 is also useful in this indication.

The protein IGF2BP3 is linked to gastric cancer (Wang et al., 2010;Okada et al., 2012), hepatocellular carcinoma (Wachter et al., 2012),tongue squamous cell carcinoma (Li et al., 2011a), oral cancer (Hwang etal., 2012), and renal cell carcinoma (Jiang et al., 2006),hepatocellular carcinoma (Riener, 2011), invasive squamous cellcarcinoma (Lu et al., 2011), neuroblastoma (Chen et al., 2011), squamouscell carcinoma of the lung (Kobayashi et al., 2004; Findeis-Hosey andXu, 2012), glioblastoma (Suvasini et al., 2011), pancreatic ductaladenocarcinoma (Yantiss et al., 2008; Schaeffer et al., 2010; Wachter etal., 2011), primary adenoid cystic carcinomas of the breast (Vranic etal., 2011), prostate carcinomas (Ikenberg et al., 2010), thyroidcarcinomas (Jin et al., 2010), endometrioid adenocarcinoma (Li et al.,2007), melanoma (Pryor et al., 2008) and ovarian cancer (Gu et al.,2004) and therefore the peptide SEQ ID No 66 is also useful in theseindications.

The protein DROSHA is linked to breast cancer (Passon et al., 2012),with ovarian cancer (Merritt et al., 2008), endometrial cancer (Torreset al., 2011), cervical cancer (Zhou et al., 2013), gastric cancer(Tchernitsa et al., 2010), colorectal carcinoma (Papachristou et al.,2011), bladder cancer (Han et al., 2013), esophageal cancers (Sugito etal., 2006), renal cell carcinoma (Lin et al., 2010b), lung cancersurvival (Rotunno et al., 2010), and therefore the peptide SEQ ID No 67is also useful in these indications.

The protein ABCA13 is linked to breast carcinoma (Hlavac et al., 2013),colorectal carcinoma (Hlavata et al., 2012) and therefore the peptideSEQ ID No 68 is also useful in these indications. The protein CCNB1 islinked to colorectal carcinoma (Li et al., 2003), RCC(Tsavachidou-Fenner et al., 2010), breast cancer (Aaltonen et al., 2009;Agarwal et al., 2009; Suzuki et al., 2007; Chae et al., 2011),medulloblastoma (de et al., 2008), squamous cell lung cancer (Kettunenet al., 2004), gastrointestinal stromal tumors (Koon et al., 2004),esophageal squamous cell carcinoma (Song et al., 2008), laryngealsquamous cell carcinoma (Dong et al., 2002), oral tongue squamous cellcarcinoma (Harada et al., 2006), adrenocortical carcinomas (Soon et al.,2009), pulmonary adenocarcinoma (Wikman et al., 2002), non-small celllung cancer (Cooper et al., 2009), cervical cancer (Zhao et al., 2006),prolactin pituitary tumors (Raverot et al., 2010) and renal cellcarcinoma (Ikuerowo et al., 2006) and therefore the peptide SEQ ID No 69is also useful in these indications.

The protein CNOT1 is linked to breast cancer (Winkler et al., 2006) andtherefore the peptide SEQ ID No 70 is also useful in this indication.

The protein BIRC5 is linked to breast cancer (Yamashita et al., 2007;Al-Joudi et al., 2007; Span et al., 2004), esophageal cancer (Sato etal., 2006), colorectal cancer (Tan et al., 2005), clear cell renal cellcarcinoma (Kosari et al., 2005), pancreatic cancer (Mahlamaki et al.,2002), squamous cell carcinoma (Lo et al., 2001), lung cancer (Krepelaet al., 2009) and in neuroblastoma (Lamers et al., 2011) and thereforethe peptide SEQ ID No 72 is also useful in these indications.

The protein ZNF3 is linked to head and neck squamous cell carcinoma(Nichols et al., 2012) and therefore the peptide SEQ ID No 81 is alsouseful in this indication.

The protein PJA2 is linked to thyroid cancer (Cantara et al., 2012) andtherefore the peptide SEQ ID No 84 is also useful in this indication.

The protein GPM6B is linked to ovarian cancer (Urban et al., 2011) andtherefore the peptide SEQ ID No 86 is also useful in this indication.

The protein OLIG2 is linked to breast cancer (Kamalakaran et al., 2011)and therefore the peptide SEQ ID No 91 is also useful in thisindication.

The protein VCAN is linked to ovarian cancer (Zhang et al., 2012),breast cancer (Nara et al., 1997), colon cancer (Yoon et al., 2002),skin cancer (Kunisada et al., 2011), lung cancer (Rotunno et al., 2011),renal cell carcinoma (Dondeti et al., 2012) and therefore the peptideSEQ ID No 92 is also useful in these indications.

The protein SMOX is linked to prostate cancer (Goodwin et al., 2008),breast cancer (Cervelli et al., 2010) and therefore the peptide SEQ IDNo 93 is also useful in these indications.

The protein EXOC7 is linked to breast cancer (Yau et al., 2010) andtherefore the peptide SEQ ID No 94 is also useful in this indication.

The protein LZTS1 is linked to prostate cancer (Hawkins et al., 2002),lung cancer (Lin et al., 2013), bladder cancer (Abraham et al., 2007)and breast cancer (Chen et al., 2009) and therefore the peptide SEQ IDNo 95 is also useful in these indications.

The protein FADS2 is linked to hepatocellular carcinoma (Muir et al.,2013), breast cancer (Pender-Cudlip et al., 2013) and therefore thepeptide SEQ ID No 96 is also useful in this indication.

The protein ASCL1 is linked to lung cancer (Borges et al., 1997; Jianget al., 2004; Osada et al., 2005), neuroblastomas (Singh et al., 2004),medullary thyroid carcinomas (Kastan et al., 1990), breast cancer (Righiet al., 2012), prostate cancer (Rapa et al., 2008), gastrointestinalNECs (Shida et al., 2005) and therefore the peptide SEQ ID No 98 is alsouseful in these indications.

The protein NKAIN2 is linked to prostate cancer (Mao et al., 2011) andtherefore the peptide SEQ ID No 100 is also useful in this indication.

The protein PCDHG A12 is linked to bladder cancer (Reinert et al.,2011), lung cancer (Lu et al., 2006), the protein PCDHGC3 is linked tocolorectal carcinoma (Dallosso et al., 2012), the protein PCDHGC4 islinked to neuroblastoma (Abe et al., 2008), the protein PCDHGB6 islinked to breast cancer (Miyamoto et al., 2005), and therefore thepeptide SEQ ID No 101 is also useful in these indications.

The protein ARHGAP21 is linked to head and neck squamous cell carcinoma(Lazarini et al., 2013) and therefore the peptide SEQ ID No 102 is alsouseful in this indication.

The protein PNMA2 is linked to testicular cancer (Mathew et al., 2007),breast cancer (Sahashi et al., 2003), lung cancer (Barnett et al.,2001), small intestine neuroendocrine tumors and liver metastasis (Lejaet al., 2009) and therefore the peptide SEQ ID No 103 is also useful inthese indications.

The protein APC is linked to sporadic colorectal and gastric cancers(Rubinfeld et al., 1993), lung cancer (Usadel et al., 2002), breastcancer (Van, I et al., 2008), bladder cancer (Ellinger et al., 2008),prostate cancer (Richiardi et al., 2013), and therefore the peptide SEQID No 105 is also useful in these indications.

The protein WASL is linked to breast cancer (Escudero-Esparza et al.,2012), esophageal squamous cell carcinomas (Li et al., 2013a),hepatocellular carcinoma (Jin et al., 2013) and therefore the peptideSEQ ID No 106 is also useful in these indications.

The protein BMP7 is linked to esophageal squamous cell carcinoma (Megumiet al., 2012), gastric cancer (Aoki et al., 2011), hepatocellularcarcinoma (Li et al., 2013a), CRC (Motoyama et al., 2008), lung cancer(Liu et al., 2012b), prostate cancer (Kobayashi et al., 2011), breastcancer (Rodriguez-Martinez et al., 2011), melanoma (Na et al., 2009),and therefore the peptide SEQ ID No 112 is also useful in theseindications.

The protein ITGA7 is linked to melanoma (Kramer et al., 1989), squamouscell carcinoma of the tongue (Carinci et al., 2005), oral squamous cellcarcinoma (Richter et al., 2011), hepatocellular carcinoma (Ren et al.,2007) and therefore the peptide SEQ ID No 113 is also useful in theseindications.

The protein RPL7A is linked to colorectal cancer (Wang et al., 2000),prostate cancer (Vaarala et al., 1998) and therefore the peptide SEQ IDNo 114 is also useful in these indications.

The protein HS2ST1 is linked to prostate cancer (Ferguson and Datta,2011) and therefore the peptide SEQ ID No 115 is also useful in thisindication.

The protein VIM is linked to prostate cancer (Burch et al., 2013),gastric cancer (Zhao et al., 2013), esophageal squamous cell carcinoma(Jin et al., 2010), hepatocellular carcinoma (Hu et al., 2004),colorectal cancer (Shirahata et al., 2009), pancreatic cancer (Zou etal., 2007), breast cancer (Gilles et al., 2003), melanoma (Hendrix etal., 1992), lung cancer (Upton et al., 1986), cervical cancer (Gilles etal., 1996), clear cell renal cell carcinoma (Williams et al., 2009),certain type of lymphomas (Gustmann et al., 1991), papillary thyroidcarcinoma (Yamamoto et al., 1992) and endometrial carcinomas (Coppola etal., 1998) and therefore the peptide SEQ ID No 116 is also useful inthese indications.

The protein CDCA7L is linked to metastatic medulloblastoma (Zhou et al.,2010) and therefore the peptide SEQ ID No 119 is also useful in thisindication.

The protein SCARA3 is linked to ovarian cancer (Bock et al., 2012) andtherefore the peptide SEQ ID No 120 is also useful in this indication.

The protein SSR1 is linked to neuroectodermal tumors (Johnson et al.,2013) and therefore the peptide SEQ ID No 121 is also useful in thisindication.

The protein NR0B1 is linked to endometrial carcinoma (Saito et al.,2005), ovarian carcinoma (Abd-Elaziz et al., 2003), prostatic carcinoma(Nakamura et al., 2009), and Ewing's sarcoma (Mendiola et al., 2006;Camoes et al., 2012; Kinsey et al., 2006), lung adenocarcinoma (Oda etal., 2009) and therefore the peptide SEQ ID No 122 is also useful inthese indications.

The protein EP400 is linked to colon cancer (Mattera et al., 2009) andtherefore the peptide SEQ ID No 124 is also useful in this indication.

The protein KIF1B is linked to hepatocellular carcinoma (Casper et al.,2011), neuroblastomas (Caren et al., 2005; Ohira et al., 2000; Nagai etal., 2000), gastric cancer invasion (Dong et al., 2013) and thereforethe peptides SEQ ID No 125 and No 128 are also useful in theseindications.

The protein RHOBTB3 is linked to in kidney and breast cancers (Bertholdet al., 2008a) and therefore the peptide SEQ ID No 126 is also useful inthese indications.

The protein KIF7 is linked to gastric cancer and pancreatic cancer(Katoh and Katoh, 2005) and therefore the peptide SEQ ID No 127 is alsouseful in these indications.

The protein MAPK6 is linked to oral cancer, colorectal cancer, gastriccancer, breast cancer, melanoma and lung cancer (Kostenko et al., 2012)and therefore the peptide SEQ ID No 129 is also useful in theseindications.

The protein ASPM is linked to hepatocellular carcinoma (Lin et al.,2008), medulloblastoma (Vulcani-Freitas et al., 2011; Salsano et al.,2012), lung cancer (Jung et al., 2009), ovarian cancer(Bruning-Richardson et al., 2011), and therefore the peptide SEQ ID No130 is also useful in these indications.

The protein SMC4 is linked to breast cancers, prostate cancers, coloncancers, and pancreatic cancers (Egland et al., 2006) and therefore thepeptide SEQ ID No 131 is also useful in these indications.

Preferred is the use of a peptide according to the present invention,the nucleic acid, the TCR, the antibody or the expression vectoraccording to the present invention, the cell according to the presentinvention, or an activated cytotoxic T lymphocyte produced according tothe present invention for the treatment of cancer or for the manufactureof a medicament against cancer, wherein said medicament preferably is avaccine. Preferably, said cancer is selected from astrocytoma, pilocyticastrocytoma, dysembryoplastic neuroepithelial tumor, oligodendrogliomas,ependymoma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas,medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma,gangliogliomas, gangliocytoma, central gangliocytoma, primitiveneuroectodermal tumors (PNET, e.g. medulloblastoma, medulloepithelioma,neuroblastoma, retinoblastoma, ependymoblastoma), tumors of the pinealparenchyma (e.g. pineocytoma, pineoblastoma), ependymal cell tumors,choroid plexus tumors, neuroepithelial tumors of uncertain origin (e.g.gliomatosis cerebri, astroblastoma), glioblastoma prostate tumor, breastcancer, esophageal cancer, colon cancer, colorectal cancer, renal cellcarcinoma, clear cell renal cell carcinoma, lung cancer, CNS, ovarian,melanoma pancreatic cancer, squamous cell carcinoma, leukemia andmedulloblastoma, and other tumors or cancers showing an overexpressionof survivin and/or the other proteins as described herein.

Another aspect of the present invention relates to a kit, comprising:(a) a container that contains a pharmaceutical composition containing apeptide according to the present invention, the nucleic acid or theexpression vector according to the present invention, a cell accordingto the present invention, or an activated cytotoxic T lymphocyteaccording to the present invention, in solution or in lyophilized form;(b) optionally, a second container containing a diluent orreconstituting solution for the lyophilized formulation; (c) optionally,at least one peptide selected from the group consisting of the peptidesaccording to SEQ ID NOs 1 to 131, and (d) optionally, instructions forthe use of the solution and/or the reconstitution and/or use of thelyophilized formulation.

Yet another aspect of the present invention relates to a method forproducing a recombinant antibody specifically binding to a human majorhistocompatibility complex (MHC) class I or II being complexed with aHLA-restricted antigen, the method comprising: immunizing a geneticallyengineered non-human mammal comprising cells expressing said human majorhistocompatibility complex (MHC) class I or II with a soluble form of aMHC class I or II molecule being complexed with said HLA-restrictedantigen; isolating mRNA molecules from antibody producing cells of saidnon-human mammal; producing a phage display library displaying proteinmolecules encoded by said mRNA molecules; and isolating at least onephage from said phage display library, said at least one phagedisplaying said antibody specifically bindable to said human majorhistocompatibility complex (MHC) class I or II being complexed with saidHLA-restricted antigen.

Yet another aspect of the present invention relates to an antibody thatspecifically binds to a peptide according to the present invention,preferably that specifically binds to a human major histocompatibilitycomplex (MHC) class I or II being complexed with the HLA-restrictedantigen and/or the peptide according to the present invention, whereinthe antibody preferably is a polyclonal antibody, monoclonal antibodyand/or a chimeric antibody.

The term “peptide” is used herein to designate a series of amino acidresidues, connected one to the other typically by peptide bonds betweenthe alpha-amino and carbonyl groups of the adjacent amino acids. Thepeptides are preferably 9 amino acids in length, but can be as short as8 amino acids in length, and as long as 10, 11, 12, 13 or 14 and in caseof MHC class II peptides they can be as long as 15, 16, 17, 18, 19, 20,21, 22 or 23 amino acids in length.

Furthermore, the term “peptide” shall include salts of a series of aminoacid residues, connected one to the other typically by peptide bondsbetween the alpha-amino and carbonyl groups of the adjacent amino acids.Preferably the salts are pharmaceutical acceptable salts.

The term “peptide” shall also include “oligopeptide”. The term“oligopeptide” is used herein to designate a series of amino acidresidues, connected one to the other typically by peptide bonds betweenthe alpha-amino and carbonyl groups of the adjacent amino acids. Thelength of the oligopeptide is not critical to the invention, as long asthe correct epitope or epitopes are maintained therein. Theoligopeptides are typically less than about 30 amino acid residues inlength, and greater than about 15 amino acids in length.

The term “polypeptide” designates a series of amino acid residues,connected one to the other typically by peptide bonds between thealpha-amino and carbonyl groups of the adjacent amino acids. The lengthof the polypeptide is not critical to the invention as long as thecorrect epitopes are maintained. In contrast to the terms peptide oroligopeptide, the term polypeptide is meant to refer to moleculescontaining more than about 30 amino acid residues.

A peptide, oligopeptide, protein or polynucleotide coding for such amolecule is “immunogenic” (and thus is an “immunogen” within the presentinvention), if it is capable of inducing an immune response. In the caseof the present invention, immunogenicity is more specifically defined asthe ability to induce a T-cell response. Thus, an “immunogen” would be amolecule that is capable of inducing an immune response, and in the caseof the present invention, a molecule capable of inducing a T-cellresponse.

A class I T cell “epitope” requires a short peptide that is bound to aclass I MHC receptor, forming a ternary complex (MHC class I alphachain, beta-2-microglobulin, and peptide) that can be recognized by a Tcell bearing a matching T-cell receptor binding to the MHC/peptidecomplex with appropriate affinity. Peptides binding to MHC class Imolecules are typically 8 to 14 amino acids in length, and mosttypically 9 amino acids in length.

In humans there are three different genetic loci that encode MHC class Imolecules (the MHC-molecules of the human are also designated humanleukocyte antigens (HLA)): HLA-A, HLA-B, and HLA-C. HLA-A*01, HLA-A*02,and HLA-B*07 are examples of different MHC class I alleles that can beexpressed from these loci.

For therapeutic and diagnostic purposes, a peptide that binds withappropriate affinity to several different HLA class II receptors ishighly desirable. A peptide binding to several different HLA class IImolecules is called a promiscuous binder.

As used herein, reference to a DNA sequence includes both singlestranded and double stranded DNA. Thus, the specific sequence, unlessthe context indicates otherwise, refers to the single strand DNA of suchsequence, the duplex of such sequence with its complement (doublestranded DNA) and the complement of such sequence. The term “codingregion” refers to that portion of a gene which either naturally ornormally codes for the expression product of that gene in its naturalgenomic environment, i.e., the region coding in vivo for the nativeexpression product of the gene.

The coding region can be from a non-mutated (“normal”), mutated oraltered gene, or can even be from a DNA sequence, or gene, whollysynthesized in the laboratory using methods well known to those of skillin the art of DNA synthesis.

The term “nucleotide sequence” refers to a heteropolymer ofdeoxyribonucleotides.

The nucleotide sequence coding for a particular peptide, oligopeptide,or polypeptide may be naturally occurring or they may be syntheticallyconstructed. Generally, DNA segments encoding the peptides,polypeptides, and proteins of this invention are assembled from cDNAfragments and short oligonucleotide linkers, or from a series ofoligonucleotides, to provide a synthetic gene that is capable of beingexpressed in a recombinant transcriptional unit comprising regulatoryelements derived from a microbial or viral operon.

As used herein the term “a nucleotide coding for a peptide” refers to anucleotide sequence coding for the peptide including artificial(man-made) start and stop codons compatible for the biological systemthe sequence is going to be expressed.

The term “expression product” means the polypeptide or protein that isthe natural translation product of the gene and any nucleic acidsequence coding equivalents resulting from genetic code degeneracy andthus coding for the same amino acid(s).

The term “fragment”, when referring to a coding sequence, means aportion of DNA comprising less than the complete coding region, whoseexpression product retains essentially the same biological function oractivity as the expression product of the complete coding region.

The term “DNA segment” refers to a DNA polymer, in the form of aseparate fragment or as a component of a larger DNA construct, which hasbeen derived from DNA isolated at least once in substantially pure form,i.e., free of contaminating endogenous materials and in a quantity orconcentration enabling identification, manipulation, and recovery of thesegment and its component nucleotide sequences by standard biochemicalmethods, for example, by using a cloning vector. Such segments areprovided in the form of an open reading frame uninterrupted by internalnon-translated sequences, or introns, which are typically present ineukaryotic genes. Sequences of non-translated DNA may be presentdownstream from the open reading frame, where the same do not interferewith manipulation or expression of the coding regions.

The term “primer” means a short nucleic acid sequence that can be pairedwith one strand of DNA and provides a free 3′OH end at which a DNApolymerase starts synthesis of a deoxyribonucleotide chain.

The term “promoter” means a region of DNA involved in binding of RNApolymerase to initiate transcription.

The term “isolated” means that the material is removed from its originalenvironment (e.g., the natural environment if it is naturallyoccurring). For example, a naturally-occurring polynucleotide orpolypeptide present in a living animal is not isolated, but the samepolynucleotide or polypeptide, separated from some or all of thecoexisting materials in the natural system, is isolated. Suchpolynucleotides could be part of a vector and/or such polynucleotides orpolypeptides could be part of a composition, and still be isolated inthat such vector or composition is not part of its natural environment.

The polynucleotides, and recombinant or immunogenic polypeptides,disclosed in accordance with the present invention may also be in“purified” form. The term “purified” does not require absolute purity;rather, it is intended as a relative definition, and can includepreparations that are highly purified or preparations that are onlypartially purified, as those terms are understood by those of skill inthe relevant art. For example, individual clones isolated from a cDNAlibrary have been conventionally purified to electrophoretichomogeneity. Purification of starting material or natural material to atleast one order of magnitude, preferably two or three orders, and morepreferably four or five orders of magnitude is expressly contemplated.Furthermore, a claimed polypeptide which has a purity of preferably99.999%, or at least 99.99% or 99.9%; and even desirably 99% by weightor greater is expressly contemplated. The polypeptides can be in aqueoussolution and the purity is than defined by compound purity not taking inaccount water and determinants used for the solution.

The nucleic acids and polypeptide expression products disclosedaccording to the present invention, as well as expression vectorscontaining such nucleic acids and/or such polypeptides, may be in“enriched form”. As used herein, the term “enriched” means that theconcentration of the material is at least about 2, 5, 10, 100, or 1000times its natural concentration (for example), advantageously 0.01%, byweight, preferably at least about 0.1% by weight. Enriched preparationsof about 0.5%, 1%, 5%, 10%, and 20% by weight are also contemplated. Thesequences, constructs, vectors, clones, and other materials comprisingthe present invention can advantageously be in enriched or isolatedform.

The term “active fragment” means a fragment that generates an immuneresponse (i.e., has immunogenic activity) when administered, alone oroptionally with a suitable adjuvant, to an animal, such as a mammal, forexample, a rabbit or a mouse, and also including a human, such immuneresponse taking the form of stimulating a T-cell response within therecipient animal, such as a human. Alternatively, the “active fragment”may also be used to induce a T-cell response in vitro.

As used herein, the terms “portion”, “segment” and “fragment,” when usedin relation to polypeptides, refer to a continuous sequence of residues,such as amino acid residues, which sequence forms a subset of a largersequence. For example, if a polypeptide were subjected to treatment withany of the common endopeptidases, such as trypsin or chymotrypsin, theoligopeptides resulting from such treatment would represent portions,segments or fragments of the starting polypeptide. When used in relationto polynucleotides, these terms refer to the products produced bytreatment of said polynucleotides with any of the endonucleases.

In accordance with the present invention, the term “percent identity” or“percent identical”, when referring to a sequence, means that a sequenceis compared to a claimed or described sequence after alignment of thesequence to be compared (the “Compared Sequence”) with the described orclaimed sequence (the “Reference Sequence”). The Percent Identity isthen determined according to the following formula:

Percent Identity=100[I−(C/R)]

wherein C is the number of differences between the Reference Sequenceand the Compared Sequence over the length of alignment between theReference Sequence and the Compared Sequence, wherein

(i) each base or amino acid in the Reference Sequence that does not havea corresponding aligned base or amino acid in the Compared Sequence and

(ii) each gap in the Reference Sequence and

(iii) each aligned base or amino acid in the Reference Sequence that isdifferent from an aligned base or amino acid in the Compared Sequence,constitutes a difference; and R is the number of bases or amino acids inthe Reference Sequence over the length of the alignment with theCompared Sequence with any gap created in the Reference Sequence alsobeing counted as a base or amino acid.

If an alignment exists between the Compared Sequence and the ReferenceSequence for which the percent identity as calculated above is aboutequal to or greater than a specified minimum Percent Identity then theCompared Sequence has the specified minimum percent identity to theReference Sequence even though alignments may exist in which the hereinabove calculated Percent Identity is less than the specified PercentIdentity.

The original peptides disclosed herein can be modified by thesubstitution of one or more residues at different, possibly selective,sites within the peptide chain, if not otherwise stated. Preferablythese substitutions are located at the end of the amino acid chain. Suchsubstitutions may be of a conservative nature, for example, where oneamino acid is replaced by an amino acid of similar structure andcharacteristics, such as where a hydrophobic amino acid is replaced byanother hydrophobic amino acid. Even more conservative would bereplacement of amino acids of the same or similar size and chemicalnature, such as where leucine is replaced by isoleucine. In studies ofsequence variations in families of naturally occurring homologousproteins, certain amino acid substitutions are more often tolerated thanothers, and these are often show correlation with similarities in size,charge, polarity, and hydrophobicity between the original amino acid andits replacement, and such is the basis for defining “conservativesubstitutions.”

Conservative substitutions are herein defined as exchanges within one ofthe following five groups: Group 1—small aliphatic, nonpolar or slightlypolar residues (Ala, Ser, Thr, Pro, Gly); Group 2—polar, negativelycharged residues and their amides (Asp, Asn, Glu, Gln); Group 3—polar,positively charged residues (H is, Arg, Lys); Group 4—large, aliphatic,nonpolar residues (Met, Leu, Ile, Val, Cys); and Group 5—large, aromaticresidues (Phe, Tyr, Trp).

Less conservative substitutions might involve the replacement of oneamino acid by another that has similar characteristics but is somewhatdifferent in size, such as replacement of an alanine by an isoleucineresidue. Highly non-conservative replacements might involve substitutingan acidic amino acid for one that is polar, or even for one that isbasic in character. Such “radical” substitutions cannot, however, bedismissed as potentially ineffective since chemical effects are nottotally predictable and radical substitutions might well give rise toserendipitous effects not otherwise predictable from simple chemicalprinciples.

Of course, such substitutions may involve structures other than thecommon L-amino acids. Thus, D-amino acids might be substituted for theL-amino acids commonly found in the antigenic peptides of the inventionand yet still be encompassed by the disclosure herein. In addition,amino acids possessing non-standard R groups (i.e., R groups other thanthose found in the common 20 amino acids of natural proteins) may alsobe used for substitution purposes to produce immunogens and immunogenicpolypeptides according to the present invention.

If substitutions at more than one position are found to result in apeptide with substantially equivalent or greater antigenic activity asdefined below, then combinations of those substitutions will be testedto determine if the combined substitutions result in additive orsynergistic effects on the antigenicity of the peptide. At most, no morethan 4 positions within the peptide would simultaneously be substituted.

The peptides of the invention can be elongated by up to four aminoacids, meaning 1, 2, 3 or 4 amino acids can be added to either end inany combination between 4:0 and 0:4. Combinations of the elongationsaccording to the invention can be depicted from the following table 3:

C-terminus N-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0 or 1 or 2 or 3 0 0or 1 or 2 or 3 or 4 N-terminus C-terminus 4 0 3 0 or 1 2 0 or 1 or 2 1 0or 1 or 2 or 3 0 0 or 1 or 2 or 3 or 4

The amino acids for the elongation can be the peptides of the originalsequence of the protein or any other amino acid. The elongation can beused to enhance the stability or solubility of the peptides.

The term “T-cell response” means the specific proliferation andactivation of effector functions induced by a peptide in vitro or invivo. For MHC class I restricted CTLs, effector functions may be lysisof peptide-pulsed, peptide-precursor pulsed or naturallypeptide-presenting target cells, secretion of cytokines, preferablyInterferon-gamma, TNF-alpha, or IL-2 induced by peptide, secretion ofeffector molecules, preferably granzymes or perforins induced bypeptide, or degranulation.

Preferably, when the CTLs specific for a peptide of SEQ ID No. 1 to SEQID No. 49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 are tested against(compared with) the substituted peptides, the peptide concentration atwhich the substituted peptides achieve half the maximal increase inlysis relative to background is no more than about 1 mM, preferably nomore than about 1 μM, more preferably no more than about 1 nM, and stillmore preferably no more than about 100 pM, and most preferably no morethan about 10 pM. It is also preferred that the substituted peptide berecognized by CTLs from more than one individual, at least two, and morepreferably three individuals.

Thus, the epitopes of the present invention may be identical tonaturally occurring tumor-associated or tumor-specific epitopes or mayinclude epitopes that differ by no more than 4 residues from thereference peptide, as long as they have substantially identicalantigenic activity. Substantially identical antigenic activity meansstimulation of T cells in comparable frequencies or numbers withcomparable avidity, effector or memory phenotype, similar responsepattern.

Stimulation of an immune response is dependent upon the presence ofantigens recognized as foreign by the host immune system. The discoveryof the existence of tumor associated antigens has now raised thepossibility of using a host's immune system to intervene in tumorgrowth. Various mechanisms of harnessing both the humoral and cellulararms of the immune system are currently explored for cancerimmunotherapy.

Specific elements of the cellular immune response are capable ofspecifically recognizing and destroying tumor cells. The isolation ofcytotoxic T-cells (CTL) from tumor-infiltrating cell populations or fromperipheral blood suggests that such cells play an important role innatural immune defences against cancer. CD8-positive T-cells inparticular, which recognize class I molecules of the majorhistocompatibility complex (MHC)-bearing peptides of usually 8 to 12residues derived from proteins or defect ribosomal products (DRIPS)located in the cytosols, play an important role in this response. TheMHC-molecules of the human are also designated as humanleukocyte-antigens (HLA).

MHC class I molecules can be found on most cells having a nucleus whichpresent peptides that result from proteolytic cleavage of mainlyendogenous, cytosolic or nuclear proteins, DRIPS, and larger peptides.However, peptides derived from endosomal compartments or exogenoussources are also frequently found on MHC class I molecules. Thisnon-classical way of class I presentation is referred to ascross-presentation in literature.

Since both types of response, CD8 and CD4 dependent, contribute jointlyand synergistically to the anti-tumor effect, the identification andcharacterization of tumor-associated antigens recognized by eitherCD8-positive CTLs (MHC class I molecule) or by CD4-positive CTLs (MHCclass II molecule) is important in the development of tumor vaccines. Itis therefore an object of the present invention, to provide compositionsof peptides that contain peptides binding to MHC complexes of eitherclass.

Considering the severe side-effects and expense associated with treatingcancer better prognosis and diagnostic methods are desperately needed.Therefore, there is a need to identify other factors representingbiomarkers for cancer in general and glioblastoma in particular.Furthermore, there is a need to identify factors that can be used in thetreatment of cancer in general and glioblastoma in particular.

The present invention provides peptides that are useful in treatingcancers/tumors, preferably brain cancers, even more preferablyglioblastoms that over- or exclusively present the peptides of theinvention. These peptides were shown by mass spectrometry to benaturally presented by HLA molecules on primary human glioblastomasamples (see example 1, and FIG. 1).

The source gene/protein (also designated “full-length protein” or“underlying protein”) from which the peptides are derived were shown tobe highly overexpressed in glioblastoma compared with normal tissues(see example 2, and FIG. 2 for glioblastoma) demonstrating a high degreeof tumor association of the source genes. Moreover, the peptidesthemselves are strongly over-presented on tumor tissue but not on normaltissues (see example 1 and FIG. 3).

HLA-bound peptides can be recognized by the immune system, specificallyT lymphocytes/T cells. T cells can destroy the cells presenting therecognized HLA/peptide complex, e.g. glioblastoma cells presenting thederived peptides.

The peptides of the present invention have been shown to be capable ofstimulating T cell responses and/or are over-presented and can be usedfor the production of antibodies and/or sTCRs according to the presentinvention (see example 3 and 1 and FIGS. 4 and 3). Thus, the peptidesare useful for generating an immune response in a patient by which tumorcells can be destroyed. An immune response in a patient can be inducedby direct administration of the described peptides or suitable precursorsubstances (e.g. elongated peptides, proteins, or nucleic acids encodingthese peptides) to the patient, ideally in combination with an agentenhancing the immunogenicity (i.e. an adjuvant). The immune responseoriginating from such a therapeutic vaccination can be expected to behighly specific against tumor cells because the target peptides of thepresent invention are not presented on normal tissues in comparable copynumbers, preventing the risk of undesired autoimmune reactions againstnormal cells in the patient.

The pharmaceutical compositions comprise the peptides either in the freeform or in the form of a pharmaceutically acceptable salt. As usedherein, “a pharmaceutically acceptable salt” refers to a derivative ofthe disclosed peptides wherein the peptide is modified by making acid orbase salts of the agent. For example, acid salts are prepared from thefree base (typically wherein the neutral form of the drug has a neutral—NH2 group) involving reaction with a suitable acid. Suitable acids forpreparing acid salts include both organic acids, e.g., acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid,malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, salicylicacid, and the like, as well as inorganic acids, e.g., hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid phosphoric acid and thelike. Conversely, preparation of basic salts of acid moieties which maybe present on a peptide are prepared using a pharmaceutically acceptablebase such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,calcium hydroxide, trimethylamine or the like.

In an especially preferred embodiment, the pharmaceutical compositionscomprise the peptides as salts of acetic acid (acetates), tri-fluoracetates or hydrochloric acid (chlorides).

In addition to being useful for treating cancer, the peptides of thepresent invention are also useful as diagnostics. Since the peptideswere generated from brain cancer cells and since it was determined thatthese peptides are not or at lower levels present in normal tissues,these peptides can be used to diagnose the presence of a cancer.

The presence of claimed peptides on tissue biopsies can assist apathologist in diagnosis of cancer. Detection of certain peptides bymeans of antibodies, mass spectrometry or other methods known in the artcan tell the pathologist that the tissue is malignant or inflamed orgenerally diseased. Presence of groups of peptides can enableclassification or sub-classification of diseased tissues. The detectionof peptides on diseased tissue specimen can enable the decision aboutthe benefit of therapies involving the immune system, especially ifT-lymphocytes are known or expected to be involved in the mechanism ofaction. Loss of MHC expression is a well described mechanism by whichinfected of malignant cells escape immunosurveillance. Thus, presence ofpeptides shows that this mechanism is not exploited by the analyzedcells.

The peptides of the present invention might be used to analyzelymphocyte responses against those peptides such as T cell responses orantibody responses against the peptide or the peptide complexed to MHCmolecules. These lymphocyte responses can be used as prognostic markersfor decision on further therapy steps. These responses can also be usedas surrogate markers in immunotherapy approaches aiming to inducelymphocyte responses by different means, e.g. vaccination of protein,nucleic acids, autologous materials, adoptive transfer of lymphocytes.In gene therapy settings, lymphocyte responses against peptides can beconsidered in the assessment of side effects. Monitoring of lymphocyteresponses might also be a valuable tool for follow-up examinations oftransplantation therapies, e.g. for the detection of graft versus hostand host versus graft diseases.

The peptides of the present invention can be used to generate anddevelop specific antibodies against MHC/peptide complexes. These can beused for therapy, targeting toxins or radioactive substances to thediseased tissue. Another use of these antibodies can be targetingradionuclides to the diseased tissue for imaging purposes such as PET.This use can help to detect small metastases or to determine the sizeand precise localization of diseased tissues.

Therefore it is a further aspect of the invention to provide a methodfor producing a recombinant antibody specifically binding to a humanmajor histocompatibility complex (MHC) class I or II being complexedwith a HLA-restricted antigen, the method comprising: immunizing agenetically engineered non-human mammal comprising cells expressing saidhuman major histocompatibility complex (MHC) class I or II with asoluble form of a MHC class I or II molecule being complexed with saidHLA-restricted antigen; isolating mRNA molecules from antibody producingcells of said non-human mammal; producing a phage display librarydisplaying protein molecules encoded by said mRNA molecules; andisolating at least one phage from said phage display library, said atleast one phage displaying said antibody specifically binding to saidhuman major histocompatibility complex (MHC) class I or II beingcomplexed with said HLA-restricted antigen.

It is a further aspect of the invention to provide an antibody thatspecifically binds to a human major histocompatibility complex (MHC)class I or II being complexed with a HLA-restricted antigen, wherein theantibody preferably is a polyclonal antibody, monoclonal antibody,bispecific antibody and/or a chimeric antibody.

Yet another aspect of the present invention then relates to a method ofproducing said antibody specifically binding to a human majorhistocompatibility complex (MHC) class I or II being complexed with aHLA-restricted antigen, the method comprising: immunizing a geneticallyengineered non-human mammal comprising cells expressing said human majorhistocompatibility complex (MHC) class I or II with a soluble form of aMHC class I or II molecule being complexed with said HLA-restrictedantigen; isolating mRNA molecules from antibody producing cells of saidnon-human mammal; producing a phage display library displaying proteinmolecules encoded by said mRNA molecules; and isolating at least onephage from said phage display library, said at least one phagedisplaying said antibody specifically bindable to said human majorhistocompatibility complex (MHC) class I or II being complexed with saidHLA-restricted antigen. Respective methods for producing such antibodiesand single chain class I major histocompatibility complexes, as well asother tools for the production of these antibodies are disclosed in WO03/068201, WO 2004/084798, WO 01/72768, WO 03/070752, and Cohen C J,Denkberg G, Lev A, Epel M, Reiter Y. Recombinant antibodies withMHC-restricted, peptide-specific, T-cell receptor-like specificity: newtools to study antigen presentation and TCR-peptide-MHC interactions. JMol Recognit. 2003 September-October; 16(5):324-32.; Denkberg G, Lev A,Eisenbach L, Benhar I, Reiter Y. Selective targeting of melanoma andAPCs using a recombinant antibody with TCR-like specificity directedtoward a melanoma differentiation antigen. J Immunol. 2003 Sep. 1;171(5):2197-207; and Cohen C J, Sarig O, Yamano Y, Tomaru U, Jacobson S,Reiter Y. Direct phenotypic analysis of human MHC class I antigenpresentation: visualization, quantitation, and in situ detection ofhuman viral epitopes using peptide-specific, MHC-restricted humanrecombinant antibodies. J Immunol. 2003 Apr. 15; 170(8):4349-61, whichfor the purposes of the present invention are all explicitlyincorporated by reference in their entireties.

Preferably, the antibody is binding with a binding affinity of below 20nanomolar, preferably of below 10 nanomolar, to the complex, which isregarded as “specific” in the context of the present invention.

It is a further aspect of the invention to provide a method forproducing a soluble T-cell receptor recognizing a specific peptide-MHCcomplex. Such soluble T-cell receptors can be generated from specificT-cell clones, and their affinity can be increased by mutagenesistargeting the complementarity-determining regions. For the purpose ofT-cell receptor selection, phage display can be used (US 2010-0113300,Liddy N, Bossi G, Adams K J, Lissina A, Mahon T M, Hassan N J, et al.Monoclonal TCR-redirected tumor cell killing. Nat Med 2012 June;18(6):980-987). For the purpose of stabilization of T-cell receptorsduring phage display and in case of practical use as drug, alpha andbeta chain can be linked e.g. by non-native disulfide bonds, othercovalent bonds (single-chain T-cell receptor), or by dimerizationdomains (see Boulter J M, et al. Stable, soluble T-cell receptormolecules for crystallization and therapeutics. Protein Eng 2003September; 16(9):707-711.; Card K F, Price-Schiavi S A, Liu B, ThomsonE, Nieves E, Belmont H, et al. A soluble single-chain T-cell receptorIL-2 fusion protein retains MHC-restricted peptide specificity and IL-2bioactivity. Cancer Immunol Immunother 2004 April; 53(4):345-357; andWillcox B E, Gao G F, Wyer J R, O'Callaghan C A, Boulter J M, Jones E Y,et al. Production of soluble alphabeta T-cell receptor heterodimerssuitable for biophysical analysis of ligand binding. Protein Sci 1999November; 8(11):2418-2423). The T-cell receptor can be linked to toxins,drugs, cytokines (see US20130115191), domains recruiting effector cellssuch as an anti-CD3 domain, etc., in order to execute particularfunctions on target cells. Moreover, it could be expressed in T cellsused for adoptive transfer. Further information can be found inWO2004033685A1 and WO2004074322A1. A combination of sTCRs is describedin WO2012056407A1. Further methods for the production are disclosed inWO2013057586A1.

In addition, they can be used to verify a pathologist's diagnosis of acancer based on a biopsied sample.

To select over-presented peptides, a presentation profile is calculatedshowing the median sample presentation as well as replicate variation.The profile juxtaposes samples of the tumor entity of interest to abaseline of normal tissue samples. Each of these profiles can then beconsolidated into an over-presentation score by calculating the p-valueof a Linear Mixed-Effects Model (J. Pinheiro, D. Bates, S. DebRoy,Sarkar D., R Core team. nlme: Linear and Nonlinear Mixed Effects Models.2008) adjusting for multiple testing by False Discovery Rate (Y.Benjamini and Y. Hochberg. Controlling the False Discovery Rate: APractical and Powerful Approach to Multiple Testing. Journal of theRoyal Statistical Society. Series B (Methodological), Vol. 57 (No.1):289-300, 1995).

In order to identify and to relatively quantify HLA ligands by massspectrometry, HLA molecules from shock-frozen tissue samples werepurified and HLA-associated peptides were isolated. The isolatedpeptides were separated and sequences were identified by onlinenano-electrospray-ionization (nanoESI) liquid chromatography-massspectrometry (LC-MS) experiments. The resulting peptide sequences wereverified by comparison of the fragmentation pattern of natural TUMAPsrecorded from glioblastoma samples with the fragmentation patterns ofcorresponding synthetic reference peptides of identical sequences. Sincethe peptides were directly identified as ligands of HLA molecules ofprimary tumors, these results provide direct evidence for the naturalprocessing and presentation of the identified peptides on primary tumortissue obtained from glioblastoma patients.

The proprietary discovery pipeline XPRESIDENT® v2.1 (see for exampleU.S. patent application Ser. No. 13/640,989 which is hereby incorporatedin its entirety) allows the identification and selection of relevantover-presented peptide vaccine candidates based on direct relativequantitation of HLA-restricted peptide levels on cancer tissues incomparison to several different non-cancerous tissues and organs. Thiswas achieved by the development of label-free differential quantitationusing the acquired LC-MS data processed by a proprietary data analysispipeline, combining algorithms for sequence identification, spectralclustering, ion counting, retention time alignment, charge statedeconvolution and normalization.

Presentation levels including error estimates for each peptide andsample were established. Peptides exclusively presented on tumor tissueand peptides over-presented in tumor versus non-cancerous tissues andorgans have been identified.

HLA-peptide complexes from 32 HLA-A*02-restricted and 13HLA-A*24-restricted shock-frozen glioblastoma tumor tissue samples werepurified and HLA-associated peptides were isolated and analyzed byLC-MS.

All TUMAPs contained in the application at hand were identified withthis approach on primary glioblastoma tumor samples confirming theirpresentation on primary glioblastoma.

TUMAPs identified on multiple glioblastoma tumor and normal tissues werequantified using ion-counting of label-free LC-MS data. The methodassumes that LC-MS signal areas of a peptide correlate with itsabundance in the sample. All quantitative signals of a peptide invarious LC-MS experiments were normalized based on central tendency,averaged per sample and merged into a bar plot, called presentationprofile. The presentation profile consolidates different analysismethods like protein database search, spectral clustering, charge statedeconvolution (decharging) and retention time alignment andnormalization.

The present invention therefore relates to a peptide comprising asequence that is selected from the group consisting of SEQ ID No. 1 toSEQ ID No. 49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 or a variantsequence thereof which is at least 90% homolog to SEQ ID No. 1 to SEQ IDNo. 49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 or a variant thereofthat induces T cells cross-reacting with said peptide, wherein saidpeptide is not a full-length polypeptide.

The present invention further relates to a peptide comprising a sequencethat is selected from the group consisting of SEQ ID No. 1 to SEQ ID No.49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 or a variant sequencethereof which is at least 90% homolog to SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71, and SEQ IDs No. 74 to 129, wherein said peptide orvariant has an overall length of between 8 and 100, preferably between 8and 30, and most preferred between 8 and 14 amino acids.

The present invention further relates to the peptides previouslydescribed, having the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class-I or -II.

The present invention further relates to the peptides previouslydescribed wherein the peptide consists or consists essentially of anamino acid sequence according to SEQ ID No. 1 to SEQ ID No. 49, SEQ IDNo. 71, and SEQ IDs No. 74 to 129 or a variant sequence thereof which isat least 90% homolog to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71,and SEQ IDs No. 74 to 129.

The present invention further relates to the peptides previouslydescribed, wherein the peptide is modified and/or includes non-peptidebonds.

The present invention further relates to the peptides previouslydescribed, wherein the peptide is a fusion protein, in particularcomprising N-terminal amino acids of the HLA-DR antigen-associatedinvariant chain (Ii).

The present invention further relates to a nucleic acid, encoding thepeptides previously described, provided, that the peptide is not thefull human protein.

The present invention further relates to the nucleic acid previouslydescribed that is DNA, cDNA, PNA, RNA or combinations thereof.

The present invention further relates to an expression vector capable ofexpressing a nucleic acid previously described.

The present invention further relates to a peptide as described before,a nucleic acid as described before or an expression vector as describedbefore for use in medicine.

The present invention further relates to a host cell comprising anucleic acid as described before or an expression vector as describedbefore.

The present invention further relates to the host cell described that isan antigen presenting cell.

The present invention further relates to the host cell described whereinthe antigen presenting cell is a dendritic cell.

The present invention further relates to a method of producing a peptidedescribed, the method comprising culturing the host cell described andisolating the peptide from the host cell or its culture medium.

The present invention further relates to an in vitro method forproducing activated cytotoxic T lymphocytes (CTL), the method comprisingcontacting in vitro CTL with antigen loaded human class I or II MHCmolecules expressed on the surface of a suitable antigen-presenting cellfor a period of time sufficient to activate said CTL in an antigenspecific manner, wherein said antigen is any peptide described.

The present invention further relates to the method as described,wherein the antigen is loaded onto class I or II MHC molecules expressedon the surface of a suitable antigen-presenting cell by contacting asufficient amount of the antigen with an antigen-presenting cell.

The present invention further relates to the method as described,wherein the antigen-presenting cell comprises an expression vectorcapable of expressing said peptide containing SEQ ID No. 1 to SEQ ID No.49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 or a variant sequencethereof which is at least 90% homolog to SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71, and SEQ IDs No. 74 to 129 or said variant amino acidsequence.

The present invention further relates to activated cytotoxic Tlymphocytes (CTL), produced by the method described, which selectivelyrecognise a cell which aberrantly expresses a polypeptide comprising anamino acid sequence described.

The present invention further relates to a method of killing targetcells in a patient which target cells aberrantly express a polypeptidecomprising any amino acid sequence described, the method comprisingadministering to the patient an effective number of cytotoxic Tlymphocytes (CTL) as defined.

The present invention further relates to the use of any peptidedescribed, a nucleic acid as described, an expression vector asdescribed, a cell as described, or an activated cytotoxic T lymphocyteas described as a medicament or in the manufacture of a medicament.

The present invention further relates to a use as described, wherein themedicament is a vaccine.

The present invention further relates to a use as described, wherein themedicament is active against cancer.

The present invention further relates to a use as described, whereinsaid cancer cells are glioblastoma or other brain tumor.

Furthermore, the present invention relates to a method for producing apersonalized anti-cancer vaccine for an individual patient using awarehouse of prescreened tumor associated peptides, preferably accordingto the present invention and/or as described herein.

The present invention further relates to particular marker proteins andbiomarkers that can be used in the prognosis of glioblastoma.

Furthermore, the present invention relates to the use of these noveltargets for cancer treatment.

The term “antibodies” is used herein in a broad sense and includes bothpolyclonal and monoclonal antibodies. In addition to intactimmunoglobulin molecules, also included in the term “antibodies” arefragments or polymers of those immunoglobulin molecules and humanizedversions of immunoglobulin molecules, so long as they exhibit any of thedesired properties (e.g., specific binding of an glioblastoma markerpolypeptide, delivery of a toxin to an glioblastoma cell expressing aglioblastoma marker gene at an increased level, and/or inhibiting theactivity of a glioblastoma marker polypeptide) described herein.

Whenever possible, the antibodies of the invention may be purchased fromcommercial sources. The antibodies of the invention may also begenerated using well-known methods. The skilled artisan will understandthat either full length glioblastoma marker polypeptides or fragmentsthereof may be used to generate the antibodies of the invention. Apolypeptide to be used for generating an antibody of the invention maybe partially or fully purified from a natural source, or may be producedusing recombinant DNA techniques.

For example, a cDNA encoding PTPRZ1, BCAN, and FABP7, or any otherpolypeptide according to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71,and SEQ IDs No. 74 to 129 or a variant sequence thereof which is atleast 90% homolog to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, andSEQ IDs No. 74 to 129, or a fragment thereof, can be expressed inprokaryotic cells (e.g., bacteria) or eukaryotic cells (e.g., yeast,insect, or mammalian cells), after which the recombinant protein can bepurified and used to generate a monoclonal or polyclonal antibodypreparation that specifically bind the glioblastoma marker polypeptideused to generate the antibody.

One of skill in the art will know that the generation of two or moredifferent sets of monoclonal or polyclonal antibodies maximizes thelikelihood of obtaining an antibody with the specificity and affinityrequired for its intended use (e.g., ELISA, immunohistochemistry, invivo imaging, immunotoxin therapy). The antibodies are tested for theirdesired activity by known methods, in accordance with the purpose forwhich the antibodies are to be used (e.g., ELISA, immunohistochemistiy,immunotherapy, etc.; for further guidance on the generation and testingof antibodies, see, e.g., Harlow and Lane, Antibodies: A LaboratoryManual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.,1988). For example, the antibodies may be tested in ELISA assays,Western blots, immunohistochemical staining of formalin-fixedglioblastoma or frozen tissue sections. After their initial in vitrocharacterization, antibodies intended for therapeutic or in vivodiagnostic use are tested according to known clinical testing methods.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a substantially homogeneous population of antibodies,i.e.; the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. The monoclonal antibodies herein specifically include“chimeric” antibodies in which a portion of the heavy and/or light chainis identical with or homologous to corresponding sequences in antibodiesderived from a particular species or belonging to a particular antibodyclass or subclass, while the remainder of the chain(s) is identical withor homologous to corresponding sequences in antibodies derived fromanother species or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired antagonistic activity (U.S. Pat. No. 4,816,567, which is herebyincorporated in its entirety).

Monoclonal antibodies of the invention may be prepared using hybridomamethods. In a hybridoma method, a mouse or other appropriate hostanimal, is typically immunized with an immunizing agent to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the immunizing agent. Alternatively, thelymphocytes may be immunized in vitro.

The monoclonal antibodies may also be made by recombinant DNA methods,such as those described in U.S. Pat. No. 4,816,567. DNA encoding themonoclonal antibodies of the invention can be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies).

In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly, Fabfragments, can be accomplished using routine techniques known in theart. For instance, digestion can be performed using papain. Examples ofpapain digestion are described in WO 94/29348 published Dec. 22, 1994and U.S. Pat. No. 4,342,566. Papain digestion of antibodies typicallyproduces two identical antigen binding fragments, called Fab fragments,each with a single antigen binding site, and a residual Fe fragment.Pepsin treatment yields a fragment that has two antigen combining sitesand is still capable of cross-linking antigen.

The antibody fragments, whether attached to other sequences or not, canalso include insertions, deletions, substitutions, or other selectedmodifications of particular regions or specific amino acids residues,provided the activity of the fragment is not significantly altered orimpaired compared to the non-modified antibody or antibody fragment.These modifications can provide for some additional property, such as toremove/add amino acids capable of disulfide bonding, to increase itsbio-longevity, to alter its secretory characteristics, etc. In any case,the antibody fragment must possess a bioactive property, such as bindingactivity, regulation of binding at the binding domain, etc. Functionalor active regions of the antibody may be identified by mutagenesis of aspecific region of the protein, followed by expression and testing ofthe expressed polypeptide. Such methods are readily apparent to askilled practitioner in the art and can include site-specificmutagenesis of the nucleic acid encoding the antibody fragment.

The antibodies of the invention may further comprise humanizedantibodies or human antibodies. Humanized forms of non-human (e.g.,murine) antibodies are chimeric immunoglobulins, immunoglobulin chainsor fragments thereof (such as Fv, Fab, Fab′ or other antigen-bindingsubsequences of antibodies) which contain minimal sequence derived fromnon-human immunoglobulin. Humanized antibodies include humanimmunoglobulins (recipient antibody) in which residues from acomplementary determining region (CDR) of the recipient are replaced byresidues from a CDR of a non-human species (donor antibody) such asmouse, rat or rabbit having the desired specificity, affinity andcapacity. In some instances, Fv framework (FR) residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin.

Methods for humanizing non-human antibodies are well known in the art.Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed by substituting rodent CDRs or CDR sequencesfor the corresponding sequences of a human antibody. Accordingly, such“humanized” antibodies are chimeric antibodies (U.S. Pat. No.4,816,567), wherein substantially less than an intact human variabledomain has been substituted by the corresponding sequence from anon-human species. In practice, humanized antibodies are typically humanantibodies in which some CDR residues and possibly some FR residues aresubstituted by residues from analogous sites in rodent antibodies.

Transgenic animals (e.g., mice) that are capable, upon immunization, ofproducing a full repertoire of human antibodies in the absence ofendogenous immunoglobulin production can be employed. For example, ithas been described that the homozygous deletion of the antibody heavychain joining region gene in chimeric and germ-line mutant mice resultsin complete inhibition of endogenous antibody production. Transfer ofthe human germ-line immunoglobulin gene array in such germ-line mutantmice will result in the production of human antibodies upon antigenchallenge. Human antibodies can also be produced in phage displaylibraries.

Antibodies of the invention are preferably administered to a subject ina pharmaceutically acceptable carrier. Typically, an appropriate amountof a pharmaceutically-acceptable salt is used in the formulation torender the formulation isotonic. Examples of thepharmaceutically-acceptable carrier include saline, Ringer's solutionand dextrose solution. The pH of the solution is preferably from about 5to about 8, and more preferably from about 7 to about 7.5. Furthercarriers include sustained release preparations such as semipermeablematrices of solid hydrophobic polymers containing the antibody, whichmatrices are in the form of shaped articles, e.g., films, liposomes ormicroparticles. It will be apparent to those persons skilled in the artthat certain carriers may be more preferable depending upon, forinstance, the route of administration and concentration of antibodybeing administered.

The antibodies can be administered to the subject, patient, or cell byinjection (e.g., intravenous, intraperitoneal, subcutaneous,intramuscular), or by other methods such as infusion that ensure itsdelivery to the bloodstream in an effective form. The antibodies mayalso be administered by intratumoral or peritumoral routes, to exertlocal as well as systemic therapeutic effects. Local or intravenousinjection is preferred.

Effective dosages and schedules for administering the antibodies may bedetermined empirically, and making such determinations is within theskill in the art. Those skilled in the art will understand that thedosage of antibodies that must be administered will vary depending on,for example, the subject that will receive the antibody, the route ofadministration, the particular type of antibody used and other drugsbeing administered. A typical daily dosage of the antibody used alonemight range from about 1 (μg/kg to up to 100 mg/kg of body weight ormore per day, depending on the factors mentioned above. Followingadministration of an antibody for treating glioblastoma, the efficacy ofthe therapeutic antibody can be assessed in various ways well known tothe skilled practitioner. For instance, the size, number, and/ordistribution of glioblastoma in a subject receiving treatment may bemonitored using standard tumor imaging techniques. Atherapeutically-administered antibody that arrests tumor growth, resultsin tumor shrinkage, and/or prevents the development of new tumors,compared to the disease course that would occurs in the absence ofantibody administration, is an efficacious antibody for treatment ofglioblastoma.

Because the glioblastoma markers PTPRZ1, BCAN, FABP7 and others of theinvention are highly expressed in glioblastoma cells and are expressedat extremely low levels in normal cells, inhibition of PTPRZ1, BCAN,FABP7 expression or polypeptide activity may be integrated into anytherapeutic strategy for treating or preventing glioblastoma.

The principle of antisense therapy is based on the hypothesis thatsequence-specific suppression of gene expression (via transcription ortranslation) may be achieved by intra-cellular hybridization betweengenomic DNA or mRNA and a complementary antisense species. The formationof such a hybrid nucleic acid duplex interferes with transcription ofthe target tumor antigen-encoding genomic DNA, orprocessing/transport/translation and/or stability of the target tumorantigen mRNA.

Antisense nucleic acids can be delivered by a variety of approaches. Forexample, antisense oligonucleotides or anti-sense RNA can be directlyadministered (e.g., by intravenous injection) to a subject in a formthat allows uptake into tumor cells. Alternatively, viral or plasmidvectors that encode antisense RNA (or RNA fragments) can be introducedinto cells in vivo. Antisense effects can also be induced by sensesequences; however, the extent of phenotypic changes is highly variable.Phenotypic changes induced by effective antisense therapy are assessedaccording to changes in, e.g., target mRNA levels, target proteinlevels, and/or target protein activity levels.

In a specific example, inhibition of lung tumor marker function byantisense gene therapy may be accomplished by direct administration ofantisense lung tumor marker RNA to a subject. The antisense tumor markerRNA may be produced and isolated by any standard technique, but is mostreadily produced by in vitro transcription using an antisense tumormarker cDNA under the control of a high efficiency promoter (e.g., theT7 promoter). Administration of anti-sense tumor marker RNA to cells canbe carried out by any of the methods for direct nucleic acidadministration described below.

In the methods described above, which include the administration anduptake of exogenous DNA into the cells of a subject (i.e., genetransduction or transfection), the nucleic acids of the presentinvention can be in the form of naked DNA or the nucleic acids can be ina vector for delivering the nucleic acids to the cells for inhibition ofgastric tumor marker protein expression. The vector can be acommercially available preparation, such as an adenovirus vector(Quantum Biotechnologies, Inc. (Laval, Quebec, Canada). Delivery of thenucleic acid or vector to cells can be via a variety of mechanisms. Asone example, delivery can be via a liposome, using commerciallyavailable liposome preparations such as LIPOFECTIN, LIPOFECTAMINE(GIBCO-25 BRL, Inc., Gaithersburg, Md.), SUPERFECT (Qiagen, Inc. Hilden,Germany) and TRANSFECTA M (Promega Biotec, Inc., Madison, Wis.), as wellas other liposomes developed according to procedures standard in theart. In addition, the nucleic acid or vector of this invention can bedelivered in vivo by electroporation, the technology for which isavailable from Genetronics, Inc. (San Diego, Calif.) as well as by meansof a SONOPORATION machine (ImaRx Pharmaceutical Corp., Tucson, Ariz.).

The antibodies may also be used for in vivo diagnostic assays.Generally, the antibody is labeled with a radionucleotide (such as¹¹¹In, ⁹⁹Tc, ¹⁴C, ¹³¹I, ³H, ³²P or ³⁵S) so that the tumor can belocalized using immunoscintiography. In one embodiment, antibodies orfragments thereof bind to the extracellular domains of two or moreantigenic (epitope) targets, and the affinity value (Kd) is less than 10μM, preferably less than 10⁻³ μM, more preferably less than 10⁻⁶ μM.

Antibodies for diagnostic use may be labeled with probes suitable fordetection by various imaging methods. Methods for detection of probesinclude, but are not limited to, fluorescence, light, confocal andelectron microscopy; magnetic resonance imaging and spectroscopy;fluoroscopy, computed tomography and positron emission tomography.Suitable probes include, but are not limited to, fluorescein, rhodamine,eosin and other fluorophores, radioisotopes, gold, gadolinium and otherlanthanides, paramagnetic iron, fluorine-18 and other positron-emittingradionuclides. Additionally, probes may be bi- or multi-functional andbe detectable by more than one of the methods listed. These antibodiesmay be directly or indirectly labeled with said probes. Attachment ofprobes to the antibodies includes covalent attachment of the probe,incorporation of the probe into the antibody, and the covalentattachment of a chelating compound for binding of probe, amongst otherswell recognized in the art. For immunohistochemistry, the disease tissuesample may be fresh or frozen or may be embedded in paraffin and fixedwith a preservative such as formalin. The fixed or embedded sectioncontains the sample are contacted with a labeled primary antibody andsecondary antibody, wherein the antibody is used to detect therespective epitopes of peptides, polypeptides and/or MHC complexes insitu.

The present invention thus provides a peptide comprising a sequence thatis selected from the group of consisting of SEQ ID No. 1 to SEQ ID No.49, SEQ ID No. 71 and SEQ IDs No. 74 to 129 or a variant sequencethereof which is at least 90% homolog to SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71 and SEQ IDs No. 74 to 129 or a variant thereof that willinduce T cells cross-reacting with said peptide.

The peptides of the invention have the ability to bind to a molecule ofthe human major histocompatibility complex (MHC) class-I and/or classII.

In the present invention, the term “homologous” refers to the degree ofidentity between sequences of two amino acid sequences, i.e. peptide orpolypeptide sequences. The aforementioned “homology” is determined bycomparing two sequences aligned under optimal conditions over thesequences to be compared. The sequences to be compared herein may havean addition or deletion (for example, gap and the like) in the optimumalignment of the two sequences. Such a sequence homology can becalculated by creating an alignment using, for example, the ClustalWalgorithm. Commonly available sequence analysis software, morespecifically, Vector NTI, GENETYX or analysis tools provided by publicdatabases.

A person skilled in the art will be able to assess, whether T cellsinduced by a variant of a specific peptide will be able to cross-reactwith the peptide itself (Fong et al., 2001); (Zaremba et al., 1997;Colombetti et al., 2006; Appay et al., 2006).

By a “variant” of the given amino acid sequence the inventors mean thatthe side chains of, for example, one or two of the amino acid residuesare altered (for example by replacing them with the side chain ofanother naturally occurring amino acid residue or some other side chain)such that the peptide is still able to bind to an HLA molecule insubstantially the same way as a peptide consisting of the given aminoacid sequence in consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71and SEQ IDs No. 74 to 129 or a variant sequence thereof which is atleast 90% homolog to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71 andSEQ IDs No. 74 to 129. For example, a peptide may be modified so that itat least maintains, if not improves, the ability to interact with andbind to the binding groove of a suitable MHC molecule, such as HLA-A*02or -DR, and in that way it at least maintains, if not improves, theability to bind to the TCR of activated CTL.

These CTL can subsequently cross-react with cells and kill cells thatexpress a polypeptide that contains the natural amino acid sequence ofthe cognate peptide as defined in the aspects of the invention. As canbe derived from the scientific literature (Rammensee et al., 1997) anddatabases (Rammensee et al., 1999), certain positions of HLA bindingpeptides are typically anchor residues forming a core sequence fittingto the binding motif of the HLA receptor, which is defined by polar,electrophysical, hydrophobic and spatial properties of the polypeptidechains constituting the binding groove. Thus one skilled in the artwould be able to modify the amino acid sequences set forth in SEQ ID No.1 to SEQ ID No. 49, SEQ ID No. 71 and SEQ IDs No. 74 to 129 or a variantsequence thereof which is at least 90% homolog to SEQ ID No. 1 to SEQ IDNo. 49, SEQ ID No. 71 and SEQ IDs No. 74 to 129, by maintaining theknown anchor residues, and would be able to determine whether suchvariants maintain the ability to bind MHC class I or II molecules. Thevariants of the present invention retain the ability to bind to the TCRof activated CTL, which can subsequently cross-react with and kill cellsthat express a polypeptide containing the natural amino acid sequence ofthe cognate peptide as defined in the aspects of the invention.

Those amino acid residues that do not substantially contribute tointeractions with the T-cell receptor can be modified by replacementwith another amino acid whose incorporation does not substantiallyaffect T-cell reactivity and does not eliminate binding to the relevantMHC. Thus, apart from the proviso given, the peptide of the inventionmay be any peptide (by which term the inventors include oligopeptide orpolypeptide), which includes the amino acid sequences or a portion orvariant thereof as given.

TABLE 4 Variants and motif of the peptides according to SEQ ID NO: 1, 2,4, 51, 56 (A*02), 74, 75, 76, 80, 81, 84 (A*24) Position 1 2 3 4 5 6 7 89 10 11 12 13 14 CSRP2-001 Peptide Code R L G I K P E S V SEQ ID 1Variant I L A M M I M L M A A A I A L A A V V I V L V A T T I T L T A QQ I Q L Q A SLC10A4-001 Peptide Code A L A F K L D E V SEQ ID 2 VariantI L A M M I M L M A A A I A L A A V V I V L V A T T I T L T A Q Q I Q LQ A MTSS1L-001 Peptide Code G L P S G A P P G V SEQ ID 4 Variant I L A MM I M L M A A A I A L A A V V I V L V A T T I T L T A Q Q I Q L Q ABCA-002 Peptide Code A L W A W P S E L SEQ ID 51 Variant V I A M V M I MM A A V A I A A A V V V I V V A T V T I T T A Q V Q I Q Q A VPS13B-001Peptide Code S L W G G D V V L SEQ ID 56 Variant V I A M V M I M M A A VA I A A A V V V I V V A T V T I T T A Q V Q I Q Q A TMEM255A-001 PeptideCode Y Y P G V I L G F SEQ ID 74 Variant I L F I F L F ST8SIA5-001Peptide Code V Y Y F H P Q Y L SEQ ID 75 Variant I F F I F F FFAM120C-001 Peptide Code M Y P Y I Y H V L SEQ ID 76 Variant I F F I F FF FABP7-002 Peptide Code E Y M K A L G V G F SEQ ID 80 Variant I L F I FL F ZNF3-001 Peptide Code K Y N D F G N S F SEQ ID 81 Variant I L F I FL F PJA2-001 Peptide Code R Y Q E S L G N T V F SEQ ID 84 Variant I L FI F L F

Longer peptides may also be suitable. It is also possible, that MHCclass I epitopes, although usually between 8-11 amino acids long, aregenerated by peptide processing from longer peptides or proteins thatinclude the actual epitope. It is preferred that the residues that flankthe actual epitope are residues that do not substantially affectproteolytic cleavage necessary to expose the actual epitope duringprocessing.

Accordingly, the present invention also provides peptides and variantsof MHC class I epitopes wherein the peptide or variant has an overalllength of between 8 and 100, preferably between 8 and 30, and mostpreferred between 8 and 14, namely 8, 9, 10, 11, 12, 13, 14 amino acids,in case of the class II binding peptides the length can also be 15, 16,17, 18, 19, 20, 21, 22 or 23 amino acids.

Of course, the peptide or variant according to the present inventionwill have the ability to bind to a molecule of the human majorhistocompatibility complex (MHC) class I. Binding of a peptide or avariant to a MHC complex may be tested by methods known in the art.

In a particularly preferred embodiment of the invention the peptideconsists or consists essentially of an amino acid sequence according SEQID No. 1 to SEQ ID No. 49, SEQ ID No. 71 and SEQ IDs No. 74 to 129 or avariant sequence thereof which is at least 90% homolog to SEQ ID No. 1to SEQ ID No. 49, SEQ ID No. 71 and SEQ IDs No. 74 to 129.

“Consisting essentially of” shall mean that a peptide according to thepresent invention, in addition to the sequence according to any SEQ IDNo. 1 to SEQ ID No. 49, SEQ ID No. 71 and SEQ IDs No. 74 to 129 or avariant sequence thereof which is at least 90% homolog to SEQ ID No. 1to SEQ ID No. 49, SEQ ID No. 71 and SEQ IDs No. 74 to 129 or a variantthereof contains additional N- and/or C-terminally located stretches ofamino acids that are not necessarily forming part of the peptide thatfunctions as an epitope for MHC molecules epitope.

Nevertheless, these stretches can be important to provide an efficientintroduction of the peptide according to the present invention into thecells. In one embodiment of the present invention, the peptide is afusion protein which comprises, for example, the 80 N-terminal aminoacids of the HLA-DR antigen-associated invariant chain (p33, in thefollowing “Ii”) as derived from the NCBI, GenBank Accession numberX00497.

In addition, the peptide or variant may be modified further to improvestability and/or binding to MHC molecules in order to elicit a strongerimmune response. Methods for such an optimization of a peptide sequenceare well known in the art and include, for example, the introduction ofreverse peptide bonds or non-peptide bonds.

In a reverse peptide bond amino acid residues are not joined by peptide(—CO—NH—) linkages but the peptide bond is reversed. Such retro-inversopeptidomimetics may be made using methods known in the art, for examplesuch as those described in Meziere et al (1997) J Immunol. 159,3230-3237, incorporated herein by reference. This approach involvesmaking pseudopeptides containing changes involving the backbone, and notthe orientation of side chains. Meziere et al (1997) show that for MHCbinding and T helper cell responses, these pseudopeptides are useful.Retro-inverse peptides, which contain NH—CO bonds instead of CO—NHpeptide bonds, are much more resistant to proteolysis.

A non-peptide bond is, for example, —CH₂—NH, —CH₂S—, —CH₂CH₂—, —CH═CH—,—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—. U.S. Pat. No. 4,897,445 provides amethod for the solid phase synthesis of non-peptide bonds (—CH₂—NH) inpolypeptide chains which involves polypeptides synthesized by standardprocedures and the non-peptide bond synthesized by reacting an aminoaldehyde and an amino acid in the presence of NaCNBH₃.

Peptides comprising the sequences described above may be synthesizedwith additional chemical groups present at their amino and/or carboxytermini, to enhance the stability, bioavailability, and/or affinity ofthe peptides. For example, hydrophobic groups such as carbobenzoxyl,dansyl, or t-butyloxycarbonyl groups may be added to the peptides' aminotermini. Likewise, an acetyl group or a 9-fluorenylmethoxy-carbonylgroup may be placed at the peptides' amino termini. Additionally, thehydrophobic group, t-butyloxycarbonyl, or an amido group may be added tothe peptides' carboxy termini.

Further, the peptides of the invention may be synthesized to alter theirsteric configuration. For example, the D-isomer of one or more of theamino acid residues of the peptide may be used, rather than the usualL-isomer. Still further, at least one of the amino acid residues of thepeptides of the invention may be substituted by one of the well-knownnon-naturally occurring amino acid residues. Alterations such as thesemay serve to increase the stability, bioavailability and/or bindingaction of the peptides of the invention.

Similarly, a peptide or variant of the invention may be modifiedchemically by reacting specific amino acids either before or aftersynthesis of the peptide. Examples for such modifications are well knownin the art and are summarized e.g. in R. Lundblad, Chemical Reagents forProtein Modification, 3rd ed. CRC Press, 2005, which is incorporatedherein by reference. Chemical modification of amino acids includes butis not limited to, modification by acylation, amidination,pyridoxylation of lysine, reductive alkylation, trinitrobenzylation ofamino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS), amidemodification of carboxyl groups and sulphydryl modification by performicacid oxidation of cysteine to cysteic acid, formation of mercurialderivatives, formation of mixed disulphides with other thiol compounds,reaction with maleimide, carboxymethylation with iodoacetic acid oriodoacetamide and carbamoylation with cyanate at alkaline pH, althoughwithout limitation thereto. In this regard, the skilled person isreferred to Chapter 15 of Current Protocols In Protein Science, Eds.Coligan et al. (John Wiley and Sons NY 1995-2000) for more extensivemethodology relating to chemical modification of proteins.

Briefly, modification of e.g. arginyl residues in proteins is oftenbased on the reaction of vicinal dicarbonyl compounds such asphenylglyoxal, 2,3-butanedione, and 1,2-cyclohexanedione to form anadduct. Another example is the reaction of methylglyoxal with arginineresidues.

Cysteine can be modified without concomitant modification of othernucleophilic sites such as lysine and histidine. As a result, a largenumber of reagents are available for the modification of cysteine. Thewebsites of companies such as Sigma-Aldrich(http://www.sigma-aldrich.com) provide information on specific reagents.

Selective reduction of disulfide bonds in proteins is also common.Disulfide bonds can be formed and oxidized during the heat treatment ofbiopharmaceuticals.

Woodward's Reagent K may be used to modify specific glutamic acidresidues. N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide can be usedto form intra-molecular crosslinks between a lysine residue and aglutamic acid residue.

For example, diethylpyrocarbonate is a reagent for the modification ofhistidyl residues in proteins. Histidine can also be modified using4-hydroxy-2-nonenal.

The reaction of lysine residues and other α-amino groups is, forexample, useful in binding of peptides to surfaces or the cross-linkingof proteins/peptides. Lysine is the site of attachment ofpoly(ethylene)glycol and the major site of modification in theglycosylation of proteins.

Methionine residues in proteins can be modified with e.g. iodoacetamide,bromoethylamine, and chloramine T.

Tetranitromethane and N-acetylimidazole can be used for the modificationof tyrosyl residues. Cross-linking via the formation of dityrosine canbe accomplished with hydrogen peroxide/copper ions.

Recent studies on the modification of tryptophan have usedN-bromosuccinimide, 2-hydroxy-5-nitrobenzyl bromide or3-bromo-3-methyl-2-(2-nitrophenylmercapto)-3H-indole (BPNS-skatole).

Successful modification of therapeutic proteins and peptides with PEG isoften associated with an extension of circulatory half-life whilecross-linking of proteins with glutaraldehyde, polyethyleneglycoldiacrylate and formaldehyde is used for the preparation of hydrogels.

Chemical modification of allergens for immunotherapy is often achievedby carbamylation with potassium cyanate.

A peptide or variant, wherein the peptide is modified or includesnon-peptide bonds is a preferred embodiment of the invention. Generally,peptides and variants (at least those containing peptide linkagesbetween amino acid residues) may be synthesized by the Fmoc-polyamidemode of solid-phase peptide synthesis as disclosed by Lu et al (1981)and references therein. Temporary N-amino group protection is affordedby the 9-fluorenylmethyloxycarbonyl (Fmoc) group. Repetitive cleavage ofthis highly base-labile protecting group is done using 20% piperidine inN, N-dimethylformamide. Side-chain functionalities may be protected astheir butyl ethers (in the case of serine threonine and tyrosine), butylesters (in the case of glutamic acid and aspartic acid),butyloxycarbonyl derivative (in the case of lysine and histidine),trityl derivative (in the case of cysteine) and4-methoxy-2,3,6-trimethylbenzenesulphonyl derivative (in the case ofarginine). Where glutamine or asparagine are C-terminal residues, use ismade of the 4,4′-dimethoxybenzhydryl group for protection of the sidechain amido functionalities. The solid-phase support is based on apolydimethyl-acrylamide polymer constituted from the three monomersdimethylacrylamide (backbone-monomer), bisacryloylethylene diamine(cross linker) and acryloylsarcosine methyl ester (functionalizingagent). The peptide-to-resin cleavable linked agent used is theacid-labile 4-hydroxymethyl-phenoxyacetic acid derivative. All aminoacid derivatives are added as their preformed symmetrical anhydridederivatives with the exception of asparagine and glutamine, which areadded using a reversedN,N-dicyclohexyl-carbodiimide/1hydroxybenzotriazole mediated couplingprocedure. All coupling and deprotection reactions are monitored usingninhydrin, trinitrobenzene sulphonic acid or isotin test procedures.Upon completion of synthesis, peptides are cleaved from the resinsupport with concomitant removal of side-chain protecting groups bytreatment with 95% trifluoroacetic acid containing a 50% scavenger mix.Scavengers commonly used include ethandithiol, phenol, anisole andwater, the exact choice depending on the constituent amino acids of thepeptide being synthesized. Also a combination of solid phase andsolution phase methodologies for the synthesis of peptides is possible(see, for example (Bruckdorfer et al., 2004) and the references as citedtherein).

Trifluoroacetic acid is removed by evaporation in vacuo, with subsequenttrituration with diethyl ether affording the crude peptide. Anyscavengers present are removed by a simple extraction procedure which onlyophilisation of the aqueous phase affords the crude peptide free ofscavengers. Reagents for peptide synthesis are generally available frome.g. Calbiochem-Novabiochem (UK) Ltd, Nottingham NG7 2QJ, UK.

Purification may be performed by any one, or a combination of,techniques such as re-crystallization, size exclusion chromatography,ion-exchange chromatography, hydrophobic interaction chromatography and(usually) reverse-phase high performance liquid chromatography usinge.g. acetonitril/water gradient separation.

Analysis of peptides may be carried out using thin layer chromatography,electrophoresis, in particular capillary electrophoresis, solid phaseextraction (CSPE), reverse-phase high performance liquid chromatography,amino-acid analysis after acid hydrolysis and by fast atom bombardment(FAB) mass spectrometric analysis, as well as MALDI and ESI-Q-TOF massspectrometric analysis.

A further aspect of the invention provides a nucleic acid (for example apolynucleotide) encoding a peptide or peptide variant of the invention.The polynucleotide may be, for example, DNA, cDNA, PNA, CNA, RNA orcombinations thereof, either single- and/or double-stranded, or nativeor stabilized forms of polynucleotides, such as, for example,polynucleotides with a phosphorothioate backbone and it may or may notcontain introns so long as it codes for the peptide. Of course, onlypeptides that contain naturally occurring amino acid residues joined bynaturally occurring peptide bonds are encodable by a polynucleotide. Astill further aspect of the invention provides an expression vectorcapable of expressing a polypeptide according to the invention.

A variety of methods have been developed to link polynucleotides,especially DNA, to vectors for example via complementary cohesivetermini. For instance, complementary homopolymer tracts can be added tothe DNA segment to be inserted to the vector DNA. The vector and DNAsegment are then joined by hydrogen bonding between the complementaryhomopolymeric tails to form recombinant DNA molecules.

Synthetic linkers containing one or more restriction sites provide analternative method of joining the DNA segment to vectors. Syntheticlinkers containing a variety of restriction endonuclease sites arecommercially available from a number of sources including InternationalBiotechnologies Inc. New Haven, Conn., USA.

A desirable method of modifying the DNA encoding the polypeptide of theinvention employs the polymerase chain reaction as disclosed by (Saikiet al., 1988)). This method may be used for introducing the DNA into asuitable vector, for example by engineering in suitable restrictionsites, or it may be used to modify the DNA in other useful ways as isknown in the art. If viral vectors are used, pox- or adenovirus vectorsare preferred.

The DNA (or in the case of retroviral vectors, RNA) may then beexpressed in a suitable host to produce a polypeptide comprising thepeptide or variant of the invention. Thus, the DNA encoding the peptideor variant of the invention may be used in accordance with knowntechniques, appropriately modified in view of the teachings containedherein, to construct an expression vector, which is then used totransform an appropriate host cell for the expression and production ofthe polypeptide of the invention. Such techniques include thosedisclosed in U.S. Pat. Nos. 4,440,859, 4,530,901, 4,582,800, 4,677,063,4,678,751, 4,704,362, 4,710,463, 4,757,006, 4,766,075, and 4,810,648.

The DNA (or in the case of retroviral vectors, RNA) encoding thepolypeptide constituting the compound of the invention may be joined toa wide variety of other DNA sequences for introduction into anappropriate host. The companion DNA will depend upon the nature of thehost, the manner of the introduction of the DNA into the host, andwhether episomal maintenance or integration is desired.

Generally, the DNA is inserted into an expression vector, such as aplasmid, in proper orientation and correct reading frame for expression.If necessary, the DNA may be linked to the appropriate transcriptionaland translational regulatory control nucleotide sequences recognized bythe desired host, although such controls are generally available in theexpression vector. The vector is then introduced into the host throughstandard techniques. Generally, not all of the hosts will be transformedby the vector. Therefore, it will be necessary to select for transformedhost cells. One selection technique involves incorporating into theexpression vector a DNA sequence, with any necessary control elements,that codes for a selectable trait in the transformed cell, such asantibiotic resistance.

Alternatively, the gene for such selectable trait can be on anothervector, which is used to co-transform the desired host cell.

Host cells that have been transformed by the recombinant DNA of theinvention are then cultured for a sufficient time and under appropriateconditions known to those skilled in the art in view of the teachingsdisclosed herein to permit the expression of the polypeptide, which canthen be recovered.

Many expression systems are known, including bacteria (for example E.coli and Bacillus subtilis), yeasts (for example Saccharomycescerevisiae), filamentous fungi (for example Aspergillus spec.), plantcells, animal cells and insect cells. Preferably, the system can bemammalian cells such as CHO cells available from the ATCC Cell BiologyCollection.

A typical mammalian cell vector plasmid for constitutive expressioncomprises the CMV or SV40 promoter with a suitable poly A tail and aresistance marker, such as neomycin. One example is pSVL available fromPharmacia, Piscataway, N.J., USA. An example of an inducible mammalianexpression vector is pMSG, also available from Pharmacia. Useful yeastplasmid vectors are pRS403-406 and pRS413-416 and are generallyavailable from Stratagene Cloning Systems, La Jolla, Calif. 92037, USA.Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integratingplasmids (YIps) and incorporate the yeast selectable markers HIS3, TRP1,LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps).CMV promoter-based vectors (for example from Sigma-Aldrich) providetransient or stable expression, cytoplasmic expression or secretion, andN-terminal or C-terminal tagging in various combinations of FLAG,3×FLAG, c-myc or MAT. These fusion proteins allow for detection,purification and analysis of recombinant protein. Dual-tagged fusionsprovide flexibility in detection.

The strong human cytomegalovirus (CMV) promoter regulatory region drivesconstitutive protein expression levels as high as 1 mg/L in COS cells.For less potent cell lines, protein levels are typically ˜0.1 mg/L. Thepresence of the SV40 replication origin will result in high levels ofDNA replication in SV40 replication permissive COS cells. CMV vectors,for example, can contain the pMB1 (derivative of pBR322) origin forreplication in bacterial cells, the b-lactamase gene for ampicillinresistance selection in bacteria, hGH polyA, and the f1 origin. Vectorscontaining the preprotrypsin leader (PPT) sequence can direct thesecretion of FLAG fusion proteins into the culture medium forpurification using ANTI-FLAG antibodies, resins, and plates. Othervectors and expression systems are well known in the art for use with avariety of host cells.

The present invention also relates to a host cell transformed with apolynucleotide vector construct of the present invention. The host cellcan be either prokaryotic or eukaryotic. Bacterial cells may bepreferred prokaryotic host cells in some circumstances and typically area strain of E. coli such as, for example, the E. coli strains DH5available from Bethesda Research Laboratories Inc., Bethesda, Md., USA,and RR1 available from the American Type Culture Collection (ATCC) ofRockville, Md., USA (No ATCC 31343). Preferred eukaryotic host cellsinclude yeast, insect and mammalian cells, preferably vertebrate cellssuch as those from a mouse, rat, monkey or human fibroblastic and coloncell lines. Yeast host cells include YPH499, YPH500 and YPH501, whichare generally available from Stratagene Cloning Systems, La Jolla,Calif. 92037, USA. Preferred mammalian host cells include Chinesehamster ovary (CHO) cells available from the ATCC as CCL61, NIH Swissmouse embryo cells NIH/3T3 available from the ATCC as CRL 1658, monkeykidney-derived COS-1 cells available from the ATCC as CRL 1650 and 293cells which are human embryonic kidney cells. Preferred insect cells areSf9 cells which can be transfected with baculovirus expression vectors.An overview regarding the choice of suitable host cells for expressioncan be found in, for example, the textbook of Paulina Balbás and ArgeliaLorence “Methods in Molecular Biology Recombinant Gene Expression,Reviews and Protocols,” Part One, Second Edition, ISBN978-1-58829-262-9, and other literature known to the person of skill.

Transformation of appropriate cell hosts with a DNA construct of thepresent invention is accomplished by well-known methods that typicallydepend on the type of vector used. With regard to transformation ofprokaryotic host cells, see, for example, Cohen et al (1972) Proc. Natl.Acad. Sci. USA 69, 2110, and Sambrook et al (1989) Molecular Cloning, ALaboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor,N.Y. Transformation of yeast cells is described in Sherman et al (1986)Methods In Yeast Genetics, A Laboratory Manual, Cold Spring Harbor, N.Y.The method of Beggs (1978) Nature 275, 104-109 is also useful. Withregard to vertebrate cells, reagents useful in transfecting such cells,for example calcium phosphate and DEAE-dextran or liposome formulations,are available from Stratagene Cloning Systems, or Life TechnologiesInc., Gaithersburg, Md. 20877, USA. Electroporation is also useful fortransforming and/or transfecting cells and is well known in the art fortransforming yeast cell, bacterial cells, insect cells and vertebratecells.

Successfully transformed cells, i.e. cells that contain a DNA constructof the present invention, can be identified by well-known techniquessuch as PCR. Alternatively, the presence of the protein in thesupernatant can be detected using antibodies.

It will be appreciated that certain host cells of the invention areuseful in the preparation of the peptides of the invention, for examplebacterial, yeast and insect cells. However, other host cells may beuseful in certain therapeutic methods. For example, antigen-presentingcells, such as dendritic cells, may usefully be used to express thepeptides of the invention such that they may be loaded into appropriateMHC molecules. Thus, the current invention provides a host cellcomprising a nucleic acid or an expression vector according to theinvention.

In a preferred embodiment the host cell is an antigen presenting cell,in particular a dendritic cell or antigen presenting cell. APCs loadedwith a recombinant fusion protein containing prostatic acid phosphatase(PAP) are currently under investigation for the treatment of prostatecancer (Sipuleucel-T) (Small et al., 2006; Rini et al., 2006).

A further aspect of the invention provides a method of producing apeptide or its variant, the method comprising culturing a host cell andisolating the peptide from the host cell or its culture medium.

In another embodiment the peptide, the nucleic acid or the expressionvector of the invention are used in medicine. For example, the peptideor its variant may be prepared for intravenous (i.v.) injection,sub-cutaneous (s.c.) injection, intradermal (i.d.) injection,intraperitoneal (i.p.) injection, intramuscular (i.m.) injection.Preferred methods of peptide injection include s.c., i.d., i.p., i.m.,and i.v. Preferred methods of DNA injection include i.d., i.m., s.c.,i.p. and i.v. Doses of e.g. between 50 μg and 1.5 mg, preferably 125 μgto 500 μg, of peptide or DNA may be given and will depend on therespective peptide or DNA. Dosages of this range were successfully usedin previous trials (Brunsvig et al., 2006; Staehler et al., 2007).

Another aspect of the present invention includes an in vitro method forproducing activated T cells, the method comprising contacting in vitro Tcells with antigen loaded human MHC molecules expressed on the surfaceof a suitable antigen-presenting cell for a period of time sufficient toactivate the T cell in an antigen specific manner, wherein the antigenis a peptide according to the invention. Preferably a sufficient amountof the antigen is used with an antigen-presenting cell.

Preferably the mammalian cell lacks or has a reduced level or functionof the TAP peptide transporter. Suitable cells that lack the TAP peptidetransporter include T2, RMA-S and Drosophila cells. TAP is thetransporter associated with antigen processing.

The human peptide loading deficient cell line T2 is available from theAmerican Type Culture Collection, 12301 Parklawn Drive, Rockville, Md.20852, USA under Catalogue No CRL 1992; the Drosophila cell lineSchneider line 2 is available from the ATCC under Catalogue No CRL19863; the mouse RMA-S cell line is described in Karre et al 1985.

Preferably, the host cell before transfection expresses substantially noMHC class I molecules. It is also preferred that the stimulator cellexpresses a molecule important for providing a co-stimulatory signal forT-cells such as any of B7.1, B7.2, ICAM-1 and LFA 3. The nucleic acidsequences of numerous MHC class I molecules and of the costimulatormolecules are publicly available from the GenBank and EMBL databases.

In case of a MHC class I epitope being used as an antigen, the T cellsare CD8-positive CTLs.

If an antigen-presenting cell is transfected to express such an epitope,preferably the cell comprises an expression vector capable of expressinga peptide containing SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71 andSEQ IDs No. 74 to 129 or a variant sequence thereof which is at least90% homolog to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71 and SEQ IDsNo. 74 to 129.

A number of other methods may be used for generating CTL in vitro. Forexample, the methods described in Peoples et al (1995) and Kawakami etal (1992) use autologous tumor-infiltrating lymphocytes in thegeneration of CTL. Plebanski et al (1995) makes use of autologousperipheral blood lymphocytes (PLBs) in the preparation of CTL. Jochmuset al (1997) describes the production of autologous CTL by pulsingdendritic cells with peptide or polypeptide, or via infection withrecombinant virus. Hill et al (1995) and Jerome et al (1993) make use ofB cells in the production of autologous CTL. In addition, macrophagespulsed with peptide or polypeptide, or infected with recombinant virus,may be used in the preparation of autologous CTL. S. Walter et al. 2003describe the in vitro priming of T cells by using artificial antigenpresenting cells (aAPCs), which is also a suitable way for generating Tcells against the peptide of choice. In this study, aAPCs were generatedby the coupling of preformed MHC:peptide complexes to the surface ofpolystyrene particles (microbeads) by biotin:streptavidin biochemistry.This system permits the exact control of the MHC density on aAPCs, whichallows to selectively elicit high- or low-avidity antigen-specific Tcell responses with high efficiency from blood samples. Apart fromMHC:peptide complexes, aAPCs should carry other proteins withco-stimulatory activity like anti-CD28 antibodies coupled to theirsurface. Furthermore such aAPC-based systems often require the additionof appropriate soluble factors, e.g. cytokines like interleukin-12.

Allogeneic cells may also be used in the preparation of T cells and amethod is described in detail in WO 97/26328, incorporated herein byreference. For example, in addition to Drosophila cells and T2 cells,other cells may be used to present antigens such as CHO cells,baculovirus-infected insect cells, bacteria, yeast, vaccinia-infectedtarget cells. In addition plant viruses may be used (see, for example,Porta et al (1994)) which describes the development of cowpea mosaicvirus as a high-yielding system for the presentation of foreignpeptides.

The activated T cells that are directed against the peptides of theinvention are useful in therapy. Thus, a further aspect of the inventionprovides activated T cells obtainable by the foregoing methods of theinvention.

Activated T cells, which are produced by the above method, willselectively recognize a cell that aberrantly expresses a polypeptidethat comprises an amino acid sequence of SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71 and SEQ IDs No. 74 to 129.

Preferably, the T cell recognizes the cell by interacting through itsTCR with the HLA/peptide-complex (for example, binding). The T cells areuseful in a method of killing target cells in a patient whose targetcells aberrantly express a polypeptide comprising an amino acid sequenceof the invention wherein the patient is administered an effective numberof the activated T cells. The T cells that are administered to thepatient may be derived from the patient and activated as described above(i.e. they are autologous T cells). Alternatively, the T cells are notfrom the patient but are from another individual. Of course, it ispreferred if the individual is a healthy individual. By “healthyindividual” the inventors mean that the individual is generally in goodhealth, preferably has a competent immune system and, more preferably,is not suffering from any disease that can be readily tested for, anddetected.

In vivo, the target cells for the CD8-positive T cells according to thepresent invention can be cells of the tumor (which sometimes express MHCclass II) and/or stromal cells surrounding the tumor (tumor cells)(which sometimes also express MHC class II; (Dengjel et al., 2006)).

The T cells of the present invention may be used as active ingredientsof a therapeutic composition. Thus, the invention also provides a methodof killing target cells in a patient whose target cells aberrantlyexpress a polypeptide comprising an amino acid sequence of theinvention, the method comprising administering to the patient aneffective number of T cells as defined above.

By “aberrantly expressed” the inventors also mean that the polypeptideis over-expressed compared to normal levels of expression or that thegene is silent in the tissue from which the tumor is derived but in thetumor it is expressed. By “over-expressed” the inventors mean that thepolypeptide is present at a level at least 1.2-fold of that present innormal tissue; preferably at least 2-fold, and more preferably at least5-fold or 10-fold the level present in normal tissue.

T cells may be obtained by methods known in the art, e.g. thosedescribed above.

Protocols for this so-called adoptive transfer of T cells are well knownin the art. Reviews can be found in (Gattinoni et al., 2006) and (Morganet al., 2006).

Any molecule of the invention, i.e. the peptide, nucleic acid, antibody,expression vector, cell, activated CTL, T-cell receptor or the nucleicacid encoding it is useful for the treatment of disorders, characterizedby cells escaping an immune response. Therefore any molecule of thepresent invention may be used as medicament or in the manufacture of amedicament. The molecule may be used by itself or combined with othermolecule(s) of the invention or (a) known molecule(s).

Preferably, the medicament of the present invention is a vaccine. It maybe administered directly into the patient, into the affected organ orsystemically i.d., i.m., s.c., i.p. and i.v., or applied ex vivo tocells derived from the patient or a human cell line which aresubsequently administered to the patient, or used in vitro to select asubpopulation of immune cells derived from the patient, which are thenre-administered to the patient. If the nucleic acid is administered tocells in vitro, it may be useful for the cells to be transfected so asto co-express immune-stimulating cytokines, such as interleukin-2. Thepeptide may be substantially pure, or combined with animmune-stimulating adjuvant (see below) or used in combination withimmune-stimulatory cytokines, or be administered with a suitabledelivery system, for example liposomes. The peptide may also beconjugated to a suitable carrier such as keyhole limpet haemocyanin(KLH) or mannan (see WO 95/18145 and Longenecker 1993). The peptide mayalso be tagged, may be a fusion protein, or may be a hybrid molecule.The peptides whose sequence is given in the present invention areexpected to stimulate CD4 or CD8 T cells. However, stimulation of CD8CTLs is more efficient in the presence of help provided by CD4 T-helpercells. Thus, for MHC Class I epitopes that stimulate CD8 CTL the fusionpartner or sections of a hybrid molecule suitably provide epitopes whichstimulate CD4-positive T cells. CD4- and CD8-stimulating epitopes arewell known in the art and include those identified in the presentinvention.

In one aspect, the vaccine comprises at least one peptide having theamino acid sequence set forth in SEQ ID No. 1 to SEQ ID No. 49, SEQ IDNo. 71 and SEQ IDs No. 74 to 129 or a variant sequence thereof which isat least 90% homolog to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71 andSEQ IDs No. 74 to 129 and at least one additional peptide, preferablytwo to 50, more preferably two to 25, even more preferably two to 20 andmost preferably two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen oreighteen peptides. The peptide(s) may be derived from one or morespecific TAAs and may bind to MHC class I molecules.

The polynucleotide may be substantially pure, or contained in a suitablevector or delivery system. The nucleic acid may be DNA, cDNA, PNA, RNAor a combination thereof. Methods for designing and introducing such anucleic acid are well known in the art. An overview is provided by e.g.(Pascolo et al., 2005). Polynucleotide vaccines are easy to prepare, butthe mode of action of these vectors in inducing an immune response isnot fully understood. Suitable vectors and delivery systems includeviral DNA and/or RNA, such as systems based on adenovirus, vacciniavirus, retroviruses, herpes virus, adeno-associated virus or hybridscontaining elements of more than one virus. Non-viral delivery systemsinclude cationic lipids and cationic polymers and are well known in theart of DNA delivery. Physical delivery, such as via a “gene-gun,” mayalso be used. The peptide or peptides encoded by the nucleic acid may bea fusion protein, for example with an epitope that stimulates T cellsfor the respective opposite CDR as noted above.

The medicament of the invention may also include one or more adjuvants.Adjuvants are substances that non-specifically enhance or potentiate theimmune response (e.g., immune responses mediated by CTLs and helper-T(T_(H)) cells to an antigen, and would thus be considered useful in themedicament of the present invention. Suitable adjuvants include, but arenot limited to, 1018 ISS, aluminium salts, AMPLIVAX®, AS15, BCG,CP-870,893, CpG7909, CyaA, dSLIM, flagellin or TLR5 ligands derived fromflagellin, FLT3 ligand, GM-CSF, IC30, IC31, Imiquimod (ALDARA®),resiquimod, ImuFact IMP321, Interleukins as IL-2, IL-13, IL-21,Interferon-alpha or -beta, or pegylated derivatives thereof, IS Patch,ISS, ISCOMATRIX, ISCOMs, JuvImmune®, LipoVac, MALP2, MF59,monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, MontanideISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions,OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel® vector system,poly(lactid co-glycolid) [PLG]-based and dextran microparticles,talactoferrin SRL172, Virosomes and other Virus-like particles, YF-17D,VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, which isderived from saponin, mycobacterial extracts and synthetic bacterialcell wall mimics, and other proprietary adjuvants such as Ribi's Detox,Quil, or Superfos. Adjuvants such as Freund's or GM-CSF are preferred.Several immunological adjuvants (e.g., MF59) specific for dendriticcells and their preparation have been described previously (Allison andKrummel, 1995; Allison and Krummel, 1995). Also cytokines may be used.Several cytokines have been directly linked to influencing dendriticcell migration to lymphoid tissues (e.g., TNF-), accelerating thematuration of dendritic cells into efficient antigen-presenting cellsfor T-lymphocytes (e.g., GM-CSF, IL-1 and IL-4) (U.S. Pat. No.5,849,589, specifically incorporated herein by reference in itsentirety) and acting as immunoadjuvants (e.g., IL-12, IL-15, IL-23,IL-7, IFN-alpha. IFN-beta) [Gabrilovich 1996].

CpG immunostimulatory oligonucleotides have also been reported toenhance the effects of adjuvants in a vaccine setting. Without beingbound by theory, CpG oligonucleotides act by activating the innate(non-adaptive) immune system via Toll-like receptors (TLR), mainly TLR9.CpG triggered TLR9 activation enhances antigen-specific humoral andcellular responses to a wide variety of antigens, including peptide orprotein antigens, live or killed viruses, dendritic cell vaccines,autologous cellular vaccines and polysaccharide conjugates in bothprophylactic and therapeutic vaccines. More importantly it enhancesdendritic cell maturation and differentiation, resulting in enhancedactivation of T_(H1) cells and strong cytotoxic T-lymphocyte (CTL)generation, even in the absence of CD4 T cell help. The T_(H1) biasinduced by TLR9 stimulation is maintained even in the presence ofvaccine adjuvants such as alum or incomplete Freund's adjuvant (IFA)that normally promote a T_(H2) bias. CpG oligonucleotides show evengreater adjuvant activity when formulated or co-administered with otheradjuvants or in formulations such as microparticles, nanoparticles,lipid emulsions or similar formulations, which are especially necessaryfor inducing a strong response when the antigen is relatively weak. Theyalso accelerate the immune response and enable the antigen doses to bereduced by approximately two orders of magnitude, with comparableantibody responses to the full-dose vaccine without CpG in someexperiments (Krieg, 2006). U.S. Pat. No. 6,406,705 B1 describes thecombined use of CpG oligonucleotides, non-nucleic acid adjuvants and anantigen to induce an antigen-specific immune response. A CpG TLR9antagonist is dSLIM (double Stem Loop Immunomodulator) by Mologen(Berlin, Germany) which is a preferred component of the pharmaceuticalcomposition of the present invention. Other TLR binding molecules suchas RNA binding TLR 7, TLR 8 and/or TLR 9 may also be used.

Other examples for useful adjuvants include, but are not limited tochemically modified CpGs (e.g. CpR, Idera), dsRNA analogues such asPoly(I:C) and derivates thereof (e.g. AmpliGen®, Hiltonol®, poly-(ICLC),poly(IC-R), poly(I:C12U), non-CpG bacterial DNA or RNA as well asimmunoactive small molecules and antibodies such as cyclophosphamide,sunitinib, Bevacizumab, celebrex, NCX-4016, sildenafil, tadalafil,vardenafil, sorafenib, temozolomide, temsirolimus, XL-999, CP-547632,pazopanib, VEGF Trap, ZD2171, AZD2171, anti-CTLA4, other antibodiestargeting key structures of the immune system (e.g. anti-CD40,anti-TGFbeta, anti-TNFalpha receptor) and SC58175, which may acttherapeutically and/or as an adjuvant. The amounts and concentrations ofadjuvants and additives useful in the context of the present inventioncan readily be determined by the skilled artisan without undueexperimentation.

Preferred adjuvants are imiquimod, resiquimod, GM-CSF, cyclophosphamide,sunitinib, bevacizumab, interferon-alpha, CpG oligonucleotides andderivates, poly-(I:C) and derivates, RNA, sildenafil, and particulateformulations with PLG or virosomes.

In a preferred embodiment, the pharmaceutical composition according tothe invention the adjuvant is selected from the group consisting ofcolony-stimulating factors, such as Granulocyte Macrophage ColonyStimulating Factor (GM-CSF, sargramostim), imiquimod, resiquimod, andinterferon-alpha.

In a preferred embodiment, the pharmaceutical composition according tothe invention the adjuvant is selected from the group consisting ofcolony-stimulating factors, such as Granulocyte Macrophage ColonyStimulating Factor (GM-CSF, sargramostim), immiquimod and resimiquimod.

In a preferred embodiment of the pharmaceutical composition according tothe invention, the adjuvant is imiquimod or resiquimod.

This composition is used for parenteral administration, such assubcutaneous, intradermal, intramuscular or oral administration. Forthis, the peptides and optionally other molecules are dissolved orsuspended in a pharmaceutically acceptable, preferably aqueous carrier.In addition, the composition can contain excipients, such as buffers,binding agents, blasting agents, diluents, flavours, lubricants, etc.The peptides can also be administered together with immune stimulatingsubstances, such as cytokines An extensive listing of excipients thatcan be used in such a composition, can be, for example, taken from A.Kibbe, Handbook of Pharmaceutical Excipients, 3. Ed. 2000, AmericanPharmaceutical Association and pharmaceutical press. The composition canbe used for a prevention, prophylaxis and/or therapy of adenomateous orcancerous diseases. Exemplary formulations can be found in EP2113253.

Nevertheless depending on the number and the physico-chemicalcharacteristics of the peptides of the invention further research isneeded to provide formulations for specific combinations of peptidesthat are stable for more than 12-18 months.

The present invention provides a medicament that useful in treatingcancer, in particular non-small cell lung carcinoma, gastric cancer,renal cell carcinoma, colon cancer, adenocarcinoma, prostate cancer,benign neoplasm and malignant melanoma.

The present invention further includes a kit comprising:

(a) a container that contains a pharmaceutical composition as describedabove, in solution or in lyophilized form;

(b) optionally a second container containing a diluent or reconstitutingsolution for the lyophilized formulation; and

(c) optionally, instructions for (i) use of the solution or (ii)reconstitution and/or use of the lyophilized formulation.

The kit may further comprise one or more of (iii) a buffer, (iv) adiluent, (v) a filter, (vi) a needle, or (v) a syringe. The container ispreferably a bottle, a vial, a syringe or test tube; and it may be amulti-use container. The pharmaceutical composition is preferablylyophilized.

Kits of the present invention preferably comprise a lyophilizedformulation of the present invention in a suitable container andinstructions for its reconstitution and/or use. Suitable containersinclude, for example, bottles, vials (e.g. dual chamber vials), syringes(such as dual chamber syringes) and test tubes. The container may beformed from a variety of materials such as glass or plastic. Preferablythe kit and/or container contain/s instructions on or associated withthe container that indicates directions for reconstitution and/or use.For example, the label may indicate that the lyophilized formulation isto be reconstituted to peptide concentrations as described above. Thelabel may further indicate that the formulation is useful or intendedfor subcutaneous administration.

The container holding the formulation may be a multi-use vial, whichallows for repeat administrations (e.g., from 2-6 administrations) ofthe reconstituted formulation. The kit may further comprise a secondcontainer comprising a suitable diluent (e.g., sodium bicarbonatesolution).

Upon mixing of the diluent and the lyophilized formulation, the finalpeptide concentration in the reconstituted formulation is preferably atleast 0.15 mg/mL/peptide (=75 μg) and preferably not more than 3mg/mL/peptide (=1500 μg). The kit may further include other materialsdesirable from a commercial and user standpoint, including otherbuffers, diluents, filters, needles, syringes, and package inserts withinstructions for use.

Kits of the present invention may have a single container that containsthe formulation of the pharmaceutical compositions according to thepresent invention with or without other components (e.g., othercompounds or pharmaceutical compositions of these other compounds) ormay have distinct container for each component.

Preferably, kits of the invention include a formulation of the inventionpackaged for use in combination with the co-administration of a secondcompound (such as adjuvants (e.g. GM-CSF), a chemotherapeutic agent, anatural product, a hormone or antagonist, an anti-angiogenesis agent orinhibitor, a apoptosis-inducing agent or a chelator) or a pharmaceuticalcomposition thereof. The components of the kit may be pre-complexed oreach component may be in a separate distinct container prior toadministration to a patient. The components of the kit may be providedin one or more liquid solutions, preferably, an aqueous solution, morepreferably, a sterile aqueous solution. The components of the kit mayalso be provided as solids, which may be converted into liquids byaddition of suitable solvents, which are preferably provided in anotherdistinct container.

The container of a therapeutic kit may be a vial, test tube, flask,bottle, syringe, or any other means of enclosing a solid or liquid.Usually, when there is more than one component, the kit will contain asecond vial or other container, which allows for separate dosing. Thekit may also contain another container for a pharmaceutically acceptableliquid. Preferably, a therapeutic kit will contain an apparatus (e.g.,one or more needles, syringes, eye droppers, pipette, etc.), whichenables administration of the agents of the invention that arecomponents of the present kit.

Another aspect of the invention then relates to a method fordistinguishing glioblastoma from other forms of cancer comprisinganalyzing the expression of PTPRZ1, BCAN, and/or FABP7 in a sampleobtained from the brain or another tumorus specimen from a subject to bediagnosed, either alone or in addition to the therapy based on themethods herein (e.g. for a monitoring). For this, another aspect of theinvention relates to s kit for measuring expression level of PTPRZ1,BCAN, and/or FABP7 as (a) glioblastoma marker gene(s), comprising atleast one antibody that specifically binds a chosen glioblastoma markerpolypeptide, or one or more nucleic acids that specifically hybridizewith PTPRZ1, BCAN, and/or FABP7 mRNA, and, optionally, a control (e.g.,a specific amount of a particular glioblastoma marker polypeptide),primary and secondary antibodies when appropriate, and optionally otherreagents, such as detectable moieties, enzyme substrates, and/or colourreagents.

The present formulation is one that is suitable for administration ofthe peptides by any acceptable route such as oral (enteral), nasal,ophthal, subcutaneous, intradermal, intramuscular, intravenous ortransdermal. Preferably the administration is s.c., and most preferably,i.d. Administration may be by infusion pump.

Since the peptides of the invention derived from SEQ ID No. 1 to SEQ IDNo. 49, SEQ ID No. 71, and SEQ IDs No. 74 to 129 were isolated fromglioblastoma, the medicament of the invention is preferably used totreat glioblastoma.

The present invention further includes a method for producing apersonalized pharmaceutical for an individual patient comprisingmanufacturing a pharmaceutical composition comprising at least onepeptide selected from a warehouse of pre-screened TUMAPs, such as, forexample the peptides according to SEQ ID No. 1 to SEQ ID No. 131, or thepeptides of the invention derived from SEQ ID No. 1 to SEQ ID No. 49,SEQ ID No. 71, and SEQ IDs No. 74 to 129 and/or other suitable tumorassociated peptides; wherein the at least one peptide used in thepharmaceutical composition is selected for suitability in the individualpatient or a small group of patients. Preferably, the pharmaceuticalcomposition is a vaccine. The method could also be adapted to produce Tcell clones for down-stream applications such as TCR isolations.

A “personalized pharmaceutical” shall mean specifically tailoredtherapies for one individual patient or a small group of patients (i.e.less than 100, preferably less than 10, more preferably less than 5,most preferred one) that will only be used for therapy in suchindividual or small group of patients, including actively personalizedcancer vaccines and adoptive cellular therapies using autologous patienttissue.

As used herein, the term “warehouse” shall refer to a group of peptidesthat have been pre-screened for immunogenicity and over-presentation ina particular tumor type or group of tumor types. The term “warehouse” isnot intended to imply that the particular peptides included in thevaccine have been pre-manufactured and stored in a physical facility,although that possibility is contemplated. It is expressly contemplatedthat the peptides may be manufactured de novo for each individualizedvaccine produced, or may be pre-manufactured and stored.

The warehouse is preferably composed of tumor-associated peptides whichwere highly overexpressed in the tumor tissue of several HLA-A*02 orHLA-A*24 positive GBM patients analyzed. It contains MHC class I and MHCclass II peptides. In addition to the tumor associated peptidescollected from several GBM tissues, the warehouse contains an HLA-A*02and an HLA-A*24 marker peptide. These peptides allow comparison of themagnitude of T-cell immunity induced by TUMAPS in a quantitative mannerand hence allow important conclusion to be drawn on the capacity of thevaccine to elicit anti-tumor responses. Secondly, it functions as animportant positive control peptide derived from a “non-self” antigen inthe case that any vaccine-induced T-cell responses to TUMAPs derivedfrom “self” antigens in a patient are not observed. And thirdly, it mayallow conclusions to be drawn, regarding the status of immunocompetenceof the patient population.

HLA class I and II TUMAPs for the warehouse are identified by using anintegrated functional genomics approach combining gene expressionanalysis, mass spectrometry, and T-cell immunology. This methodology hasbeen the basis for selection of the TUMAPs included in IMA901, IMA910 orIMA950 and the approach assures that only TUMAPs truly present on a highpercentage of tumors but not or only minimally expressed on normaltissue, are chosen for further analysis. For peptide selection,glioblastoma samples from surgically removed malignant tissue from GBMpatients and blood from healthy donors were analyzed in a stepwiseapproach:

1. HLA ligands from the malignant material were identified by massspectrometry

2. Genome-wide messenger ribonucleic acid (mRNA) expression analysis bymicroarrays was used to identify genes over-expressed in the malignanttissue (GBM) compared with a range of normal organs and tissues

3. Identified HLA ligands were compared to gene expression data.Peptides encoded by selectively expressed or over-expressed genes asdetected in step 2 were considered suitable TUMAP candidates for amulti-peptide vaccine.

4. Literature research was performed in order to identify additionalevidence supporting the relevance of the identified peptides as TUMAPs

5. The relevance of over-expression at the mRNA level was confirmed byredetection of selected TUMAPs from step 3 on tumor tissue and lack of(or infrequent) detection on healthy tissues.

6. To assess whether an induction of in vivo T-cell responses by theselected peptides may be feasible, in vitro immunogenicity assays wereperformed using human T cells from healthy donors as well as from GBMpatients.

In an aspect, the peptides are pre-screened for immunogenicity beforebeing included in the warehouse. By way of example, and not limitation,the immunogenicity of the peptides included in the warehouse isdetermined by a method comprising in vitro T-cell priming throughrepeated stimulations of CD8+ T cells from healthy donors withartificial antigen presenting cells loaded with peptide/MHC complexesand anti-CD28 antibody, as described in detail below in EXAMPLE 3.

This method is preferred for rare cancers and patients with a rareexpression profile. In contrast to multi-peptide cocktails with a fixedcomposition as currently developed the warehouse allows a significantlyhigher matching of the actual expression of antigens in the tumor withthe vaccine. Selected single or combinations of several “off-the-shelf”peptides will be used for each patient in a multitarget approach. Intheory an approach based on selection of e.g. 5 different antigenicpeptides from a library of 50 would already lead to approximately 2million possible drug product (DP) compositions.

The HLA phenotype, transcriptomic and peptidomic data will be gatheredfrom the patient's tumor material and blood samples to identify the mostsuitable peptides for each patient containing warehouse andpatient-unique (i.e. mutated) TUMAPs. Those peptides will be chosen,which are selectively or over-expressed in the patients tumor and, wherepossible, showed strong in vitro immunogenicity if tested with thepatients individual PBMCs.

In one embodiment, the warehouse comprises and/or consists of thepeptides according to SEQ ID No. 1 to 131, preferably of the peptidesaccording to the invention. Preferred additional TUMAPs presented by atumor sample from an individual patient or small group of patients areselected from the peptides described and claimed in EP1806358,EP1806359, EP1760088, EP1922335, EP2135878, EP2119726, EP2291395,GB1313987, and/or EP2138509.

Preferably, the peptides included in the vaccine are identified by amethod comprising: (a) identifying tumor-associated peptides (TUMAPs)presented by a tumor sample from the individual patient; (b) comparingthe peptides identified in (a) with a warehouse of peptides as describedabove; and (c) selecting at least one peptide from the warehouse thatcorrelates with a tumor-associated peptide identified in the patient.For example, the TUMAPs presented by the tumor sample are identified by:(a1) comparing expression data from the tumor sample to expression datafrom a sample of normal tissue corresponding to the tissue type of thetumor sample to identify proteins that are over-expressed or aberrantlyexpressed in the tumor sample; and (a2) correlating the expression datawith sequences of MHC ligands bound to MHC class I and/or class IImolecules in the tumor sample to identify MHC ligands derived fromproteins over-expressed or aberrantly expressed by the tumor.Preferably, the sequences of MHC ligands are identified by eluting boundpeptides from MHC molecules isolated from the tumor sample, andsequencing the eluted ligands. Preferably, the tumor sample and thenormal tissue are obtained from the same patient.

The peptides are selected for inclusion in the vaccine based on theirsuitability for the individual patient based on the immunogenicity,which can be determined by a method comprising in vitro immunogenicityassays, based on their level of overpresentation on the peptide level,or based on the level of overexpression of the mRNA encoding thepeptide. Preferably, the in vitro immunogenicity is determined on cellsof the individual patient.

In addition to, or as an alternative to, selecting peptides using awarehousing model, TUMAPs may be identified in the patient de novo andthen included in the vaccine. As one example, candidate TUMAPs may beidentified in the patient by (a1) comparing expression data from thetumor sample to expression data from a sample of normal tissuecorresponding to the tissue type of the tumor sample to identifyproteins that are over-expressed or aberrantly expressed in the tumorsample; and (a2) correlating the expression data with sequences of MHCligands bound to MHC class I and/or class II molecules in the tumorsample to identify MHC ligands derived from proteins over-expressed oraberrantly expressed by the tumor. As another example, proteins may beidentified containing mutations that are unique to the tumor samplerelative to normal corresponding tissue from the individual patient, andTUMAPs can be identified that specifically target the mutation. Forexample, the genome of the tumor and of corresponding normal tissue canbe sequenced by whole genome sequencing: For discovery of non-synonymousmutations in the protein-coding regions of genes, genomic DNA and RNAare extracted from tumor tissues and normal non-mutated genomic germlineDNA is extracted from peripheral blood mononuclear cells (PBMCs). Theapplied NGS approach is confined to the re-sequencing of protein codingregions (exome re-sequencing). For this purpose, exonic DNA from humansamples is captured using vendor-supplied target enrichment kits,followed by sequencing with e.g. a HiSeq2000 (Illumina). Additionally,tumor mRNA is sequenced for direct quantification of gene expression andvalidation that mutated genes are expressed in the patients' tumors. Theresultant millions of sequence reads are processed through softwarealgorithms. The output list contains mutations and gene expression.Tumor-specific somatic mutations are determined by comparison with thePBMC-derived germline variations and prioritized. The de novo identifiedpeptides may then be tested for immunogenicity as described above forthe warehouse, and candidate TUMAPs possessing suitable immunogenicityare selected for inclusion in the vaccine.

In one exemplary embodiment, the peptides included in the vaccine areidentified by: (a) identifying tumor-associated peptides (TUMAPs)presented by a tumor sample from the individual patient by the methdosdescribed above; (b) comparing the peptides identified in a) with awarehouse of peptides that have been prescreened for immunogenicity andoverpresentation in tumors as compared to corresponding normal tissue;(c) selecting at least one peptide from the warehouse that correlateswith a tumor-associated peptide identified in the patient; and (d)optionally, selecting at least one peptide identified de novo in (a)confirming its immunogenicity.

In one exemplary embodiment, the peptides included in the vaccine areidentified by: (a) identifying tumor-associated peptides (TUMAPs)presented by a tumor sample from the individual patient; and (b)selecting at least one peptide identified de novo in (a) and confirmingits immunogenicity.

Once the peptides are selected, the vaccine is manufactured. The vaccineis a liquid formulation consisting of the individual peptides dissolvedin 33% DMSO. Each peptide to be included into a product is dissolved inDMSO. The concentration of the single peptide solutions has to be chosendepending on the number of peptides to be included into the product. Thesingle peptide-DMSO solutions are mixed in equal parts to achieve asolution containing all peptides to be included in the product with aconcentration of ˜2.5 mg/ml per peptide. The mixed solution is thendiluted 1:3 with water for injection to achieve a concentration of 0.826mg/ml per peptide in 33% DMSO. The diluted solution is filtered througha 0.22 μm sterile filter. The final bulk solution is obtained. Finalbulk solution is filled into vials and stored at −20° C. until use. Onevial contains 700 μL solution containing 0.578 mg of each peptide.Thereof 500 μL (approx. 400 μg per peptide) will be applied forintradermal injection.

The present invention will now be described in the following examplesthat describe preferred embodiments thereof, nevertheless, without beinglimited thereto. For the purposes of the present invention, allreferences as cited herein are incorporated by reference in theirentireties.

EXAMPLES Example 1 Identification and Quantitation of Tumor AssociatedPeptides Presented On the Cell Surface

Tissue Samples

Patients' tumor tissues were provided by Universities of Heidelberg,University of Tübingen, both Germany, University of Geneva, Switzerland.Written informed consents of all patients had been given before surgery.Tissues were shock-frozen in liquid nitrogen immediately after surgeryand stored until isolation of TUMAPs at −80° C.

Isolation of HLA Peptides from Tissue Samples

HLA peptide pools from shock-frozen tissue samples were obtained byimmune precipitation from solid tissues according to a slightly modifiedprotocol (Falk et al., 1991; Seeger et al., 1999) using theHLA-A*02-specific antibody BB7.2, the HLA-A, -B, -C-specific antibodyW6/32, CNBr-activated sepharose, acid treatment, and ultrafiltration.

Methods

The HLA peptide pools as obtained were separated according to theirhydrophobicity by reversed-phase chromatography (Acquity UPLC system,Waters) and the eluting peptides were analyzed in an LTQ-Orbitrap hybridmass spectrometer (ThermoElectron) equipped with an ESI source. Peptidepools were loaded directly onto the analytical fused-silicamicro-capillary column (75 μm i.d.×250 mm) packed with 1.7 μm C18reversed-phase material (Waters) applying a flow rate of 400 mL perminute. Subsequently, the peptides were separated using a two-step 180minute-binary gradient from 10% to 33% B at a flow rate of 300 mL perminute. The gradient was composed of Solvent A (0.1% formic acid inwater) and solvent B (0.1% formic acid in acetonitrile). A gold coatedglass capillary (PicoTip, New Objective) was used for introduction intothe nanoESI source. The LTQ-Orbitrap mass spectrometer was operated inthe data-dependent mode using a TOPS strategy. In brief, a scan cyclewas initiated with a full scan of high mass accuracy in the orbitrap(R=30 000), which was followed by MS/MS scans also in the orbitrap(R=7500) on the 5 most abundant precursor ions with dynamic exclusion ofpreviously selected ions. Tandem mass spectra were interpreted bySEQUEST and additional manual control. The identified peptide sequencewas assured by comparison of the generated natural peptide fragmentationpattern with the fragmentation pattern of a synthetic sequence-identicalreference peptide. FIG. 1 shows an exemplary spectrum obtained fromtumor tissue for the MHC class I associated peptide IGF2BP3-001 and itselution profile on the UPLC system.

Label-free relative LC-MS quantitation was performed by ion countingi.e. by extraction and analysis of LC-MS features (Mueller et al.,2007). The method assumes that the peptide's LC-MS signal areacorrelates with its abundance in the sample. Extracted features werefurther processed by charge state deconvolution and retention timealignment (Mueller et al., 2007). Finally, all LC-MS features werecross-referenced with the sequence identification results to combinequantitative data of different samples and tissues to peptidepresentation profiles. The quantitative data were normalized in atwo-tier fashion according to central tendency to account for variationwithin technical and biological replicates. Thus each identified peptidecan be associated with quantitative data allowing relativequantification between samples and tissues. In addition, allquantitative data acquired for peptide candidates was inspected manuallyto assure data consistency and to verify the accuracy of the automatedanalysis. For each peptide a presentation profile was calculated showingthe mean sample presentation as well as replicate variations. Theprofile juxtaposes glioblastoma samples to a baseline of normal tissuesamples.

Presentation profiles of exemplary over-presented peptides are shown inFIG. 3.

Example 2 Expression Profiling of Genes Encoding the Peptides of theInvention

Not all peptides identified as being presented on the surface of tumorcells by MHC molecules are suitable for immunotherapy, because themajority of these peptides are derived from normal cellular proteinsexpressed by many cell types. Only few of these peptides aretumor-associated and likely able to induce T cells with a highspecificity of recognition for the tumor from which they were derived.In order to identify such peptides and minimize the risk forautoimmunity induced by vaccination the inventors focused on thosepeptides that are derived from proteins that are over-expressed on tumorcells compared to the majority of normal tissues.

The ideal peptide will be derived from a protein that is unique to thetumor and not present in any other tissue. To identify peptides that arederived from genes with an expression profile similar to the ideal onethe identified peptides were assigned to the proteins and genes,respectively, from which they were derived and expression profiles ofthese genes were generated.

RNA Sources and Preparation

Surgically removed tissue specimens were provided by severalinstitutions as listed in Example 1 after written informed consent hadbeen obtained from each patient. Tumor tissue specimens were snap-frozenin liquid nitrogen immediately after surgery and later homogenized withmortar and pestle under liquid nitrogen. Total RNA was prepared fromthese samples using TRI Reagent (Ambion, Darmstadt, Germany) followed bya cleanup with RNeasy (QIAGEN, Hilden, Germany); both methods wereperformed according to the manufacturer's protocol.

Total RNA from healthy human tissues was obtained commercially (Ambion,Huntingdon, UK; Clontech, Heidelberg, Germany; Stratagene, Amsterdam,Netherlands; BioChain, Hayward, Calif., USA). The RNA from severalindividuals (between 2 and 123 individuals) was mixed such that RNA fromeach individual was equally weighted.

Quality and quantity of all RNA samples were assessed on an Agilent 2100Bioanalyzer (Agilent, Waldbronn, Germany) using the RNA 6000 PicoLabChip Kit (Agilent).

Microarray Experiments

Gene expression analysis of all tumor and normal tissue RNA samples wasperformed by Affymetrix Human Genome (HG) U133A or HG-U133 Plus 2.0oligonucleotide microarrays (Affymetrix, Santa Clara, Calif., USA). Allsteps were carried out according to the Affymetrix manual. Briefly,double-stranded cDNA was synthesized from 5-8 μg of total RNA, usingSuperScript RTII (Invitrogen) and the oligo-dT-T7 primer (MWG Biotech,Ebersberg, Germany) as described in the manual. In vitro transcriptionwas performed with the BioArray High Yield RNA Transcript Labelling Kit(ENZO Diagnostics, Inc., Farmingdale, N.Y., USA) for the U133A arrays orwith the GeneChip IVT Labelling Kit (Affymetrix) for the U133 Plus 2.0arrays, followed by cRNA fragmentation, hybridization, and staining withstreptavidin-phycoerythrin and biotinylated anti-streptavidin antibody(Molecular Probes, Leiden, Netherlands). Images were scanned with theAgilent 2500A GeneArray Scanner (U133A) or the Affymetrix Gene-ChipScanner 3000 (U133 Plus 2.0), and data were analyzed with the GCOSsoftware (Affymetrix), using default settings for all parameters. Fornormalisation, 100 housekeeping genes provided by Affymetrix were used.Relative expression values were calculated from the signal log ratiosgiven by the software and the normal kidney sample was arbitrarily setto 1.0.

Exemplary expression profiles of source genes of the present inventionthat are highly over-expressed or exclusively expressed in glioblastomaare shown in FIG. 2.

Example 3 In Vitro Immunogenicity for Glioblastoma MHC Class I PresentedPeptides

In order to obtain information regarding the immunogenicity of theTUMAPs of the present invention, we performed investigations using an invitro T-cell priming assay based on repeated stimulations of CD8+ Tcells with artificial antigen presenting cells (aAPCs) loaded withpeptide/MHC complexes and anti-CD28 antibody. This way we could showimmunogenicity for 69 HLA-A*0201 and 58 HLA-A*24 restricted TUMAPs ofthe invention so far, demonstrating that these peptides are T-cellepitopes against which CD8+ precursor T cells exist in humans.

In Vitro Priming of CD8+ T Cells

In order to perform in vitro stimulations by artificial antigenpresenting cells loaded with peptide-MHC complex (pMHC) and anti-CD28antibody, we first isolated CD8+ T cells from fresh HLA-A*02leukapheresis products via positive selection using CD8 microbeads(Miltenyi Biotec, Bergisch-Gladbach, Germany) of healthy donors obtainedfrom the Transfusion Medicine Tuebingen after informed consent.

Isolated CD8+ lymphocytes or PBMCs were incubated until use in T-cellmedium (TCM) consisting of RPMI-Glutamax (Invitrogen, Karlsruhe,Germany) supplemented with 10% heat inactivated human AB serum(PAN-Biotech, Aidenbach, Germany), 100 U/ml Penicillin/100 μg/mlStreptomycin (Cambrex, Cologne, Germany), 1 mM sodium pyruvate (CC Pro,Oberdorla, Germany), 20 μg/ml Gentamycin (Cambrex). 2.5 ng/ml IL-7(PromoCell, Heidelberg, Germany) and 10 U/ml IL-2 (Novartis Pharma,Nurnberg, Germany) were also added to the TCM at this step. Generationof pMHC/anti-CD28 coated beads, T-cell stimulations and readout wasperformed in a highly defined in vitro system using four different pMHCmolecules per stimulation condition and 8 different pMHC molecules perreadout condition. All pMHC complexes used for aAPC loading andcytometric readout were derived from UV-induced MHC ligand exchange withminor modifications. In order to determine the amount of pMHC monomerobtained by exchange we performed streptavidin-based sandwich ELISAsaccording to (Rodenko et al., 2006). The purified co-stimulatory mouseIgG2a anti human CD28 Ab 9.3 (Jung et al., 1987) was chemicallybiotinylated using Sulfo-N-hydroxysuccinimidobiotin as recommended bythe manufacturer (Perbio, Bonn, Germany). Beads used were 5.6 μmdiameter streptavidin coated polystyrene particles (Bangs Laboratories,Illinois, USA).

pMHC used as controls for high immunogenic and low immunogenicstimulations were A*0201/MLA-001 (peptide ELAGIGILTV from modifiedMelan-A/MART-1) and A*0201/DDX5-001 (YLLPAIVHI from DDX5), respectively.

800.000 beads/200 μl were coated in 96-well plates in the presence of4×12.5 ng different biotin-pMHC, washed and 600 ng biotin anti-CD28 wereadded subsequently in a volume of 200 μl. Stimulations were initiated in96-well plates by co-incubating 1×10⁶ CD8+ T cells with 2×10⁵ washedcoated beads in 200 μl TCM supplemented with 5 ng/ml IL-12 (PromoCell)for 3-4 days at 37° C. Half of the medium was then exchanged by freshTCM supplemented with 80 U/ml IL-2 and incubating was continued for 3-4days at 37° C. This stimulation cycle was performed for a total of threetimes, with 12 individual wells per condition For the pMHC multimerreadout using 8 different pMHC molecules per condition, atwo-dimensional combinatorial coding approach was used as previouslydescribed (Andersen et al., 2012) with minor modifications encompassingcoupling to 5 different fluorochromes. Finally, multimeric analyses wereperformed by staining the cells with Live/dead near IR dye (Invitrogen,Karlsruhe, Germany), CD8-FITC antibody clone SK1 (BD, Heidelberg,Germany) and fluorescent pMHC multimers. For analysis, a BD LSRII SORPcytometer equipped with appropriate lasers and filters was used. Peptidespecific cells were calculated as percentage of total CD8+ cells.Evaluation of multimeric analysis was done using the FlowJo software(Tree Star, Oregon, USA). In vitro priming of specific multimer+ CD8+lymphocytes was detected by by comparison to irrelevant controlstimulations. Immunogenicity for a given antigen was detected if atleast one evaluable in vitro stimulated well of one healthy donor wasfound to contain a specific CD8+ T-cell line after in vitro stimulation(i.e. this well contained at least 1% of specific multimer+ among CD8+T-cells and the percentage of specific multimer+ cells was at least 10×the median of the irrelevant control stimulations).

In Vitro Immunogenicity for Glioblastoma Peptides

For tested HLA class I peptides, in vitro immunogenicity could bedemonstrated by generation of peptide specific T-cell lines. Exemplaryflow cytometry results after TUMAP-specific multimer staining for twopeptides of the invention are shown in FIG. 4 together withcorresponding negative controls. Results for 69 HLA-A*0201 and 58HLA-A*24 peptides from the invention are summarized in Table 5a and b.

TABLE 5a In vitro immunogenicity of HLA-A*02 class I peptides of theinvention Exemplary results of in vitro immunogenicity experimentsconducted by the applicant for the peptides of the invention. <20% = +;20%-49% = ++; 50%-70% = +++; >70% = ++++ SEQ ID NO: Peptide Code WellsDonors 68 ABCA13-001 + ++ 37 ADORA3-001 + ++ 10 ANKRD40-001 + +++ 27ASIC4-001 + ++ 51 BCA-002 ++++ ++++(100%) 13 BCA-003 + ++ 69 CCNB1-002 ++++ 45 CCT-001 + +++ 52 CDK4-001 ++ ++++ 48 CHCHD2-005 + +++ 18CLU-001 + ++ 70 CNOT1-002 + ++ 28 COL20-001 + ++ 23 CPT1C-001 + ++ 60CSP-001 + +++ 1 CSRP2-001 ++ ++++(100%) 63 DCA-001 + ++ 41 DPP3-001 ++++ 65 DPYSL4-001 + ++ 67 DROSHA-001 + ++ 29 EGFR-008 + ++ 43EIF4E-001 + +++ 3 ELOVL2-001 + ++++ 59 FABP7-001 + ++++ 21 GPR98-001 +++ 40 GRI-001 + ++ 17 GRI-002 + ++ 8 GRIK3-001 + ++++ 22 GYG2-001 + ++66 IGF2BP3-001 + +++ 32 IRS-001 + +++ 30 JAK-001 + ++ 12 KCN-002 + +++ 6KIF1A-001 ++ +++ 53 MAGEF1-001 ++ ++++ 14 MAGI2-001 + ++ 47 MAP1B-001 ++++ 35 MAP1B-002 + ++ 4 MTSS1L-001 +++ ++++(100%) 33 NAT8L-001 + ++++ 36NCAN-001 + ++++(100%) 55 NLGN4X-001 ++ ++++(100%) 39 NLGN4X-002 + ++ 11NLGN4Y-001 + ++++ 46 NOC4-001 + +++ 33 NPAS3-001 + ++ 57 NRCAM-001 +++++(100%) 61 ORMDL1-002 + +++ 7 PCDHGC5-001 + ++++(100%) 64PCNXL3-001 + ++ 44 PLEKHA4-001 + +++ 26 PTP-001 + ++ 25 PTP-002 + +++ 54PTP-003 + ++++ 50 PTP-005 ++ ++++ 15 PTP-012 + ++ 5 PTP-013 + ++++ 58RAD54B-001 ++ ++++(100%) 16 SCARA3-001 + ++ 9 SEZ6L-001 + ++++ 2SLC10A4-001 ++ +++ 20 SLC10A4-002 + +++ 24 SLC35E1-002 + ++ 49 SOX-001 +++++ 62 TACC3-001 + ++ 34 TNC-001 + ++ 42 USP11-001 ++ ++++ 56VPS13B-001 ++ ++++(100%) 31 WLS-002 + +++

TABLE 5b In vitro immunogenicity of HLA-A*24 class I peptides of theinvention Exemplary results of in vitro immunogenicity experimentsconducted by the inventors for the peptides of the invention. <20% = +;20%-49% = ++; 50%-70% = +++; >70% = ++++ SEQ ID NO: Peptide Code WellsDonors 74 TMEM255A-001 + ++ 75 ST8SIA5-001 ++ ++++ 76 FAM120C-001 ++++++(100%) 77 GRIK3-002 + ++++ 78 PTP-014 + ++ 79 PTP-019 + ++ 80FABP7-002 + ++ 81 ZNF749-001 + ++ 82 DOCK7-002 + +++ 83 LOC72839-001 ++++ 84 PJA2-001 + ++ 85 HEATR1-001 + +++ 86 GPM-002 + +++ 87 CRB1-001 +++ 88 PTP-016 + ++ 89 PTP-015 + ++ 90 PTP-018 + ++++ 91 OLIG2-001 + ++92 VCAN-003 + +++ 93 SMOX-001 + ++ 94 EXOC7-001 + ++ 95 LZTS1-001 + ++96 FADS2-003 + +++ 97 TMEM231-001 + +++ 98 ASCL1-001 + ++ 99 UNKN-003 +++ 100 NKA-001 + ++ 101 PCD-002 + ++ 102 ARHGAP21-001 + ++ 103PNMA2-001 + ++ 104 FADS2-002 + ++++ 105 APC-001 + ++ 106 WASL-001 + ++++107 SLC-002 + ++ 108 TENM4-001 + ++ 109 ZNFS3-001 ++ +++ 110EFCAB7-001 + ++ 111 DOCK7-003 + ++ 112 BMP7-001 + ++ 113 ITGA7-001 + ++114 RPL-001 + ++ 115 HS2-001 + ++ 116 VIM-002 + ++ 117 IFT17-001 + +++118 GAB-001 + ++ 119 CDCA7L-001 + ++ 120 SCARA3-002 + ++ 121 SSR1-001 +++ 122 NROB1-001 + ++ 123 LNX1-001 + ++ 124 EP4-001 + ++ 125 KIF1B-001 +++ 126 RHOBTB3-001 + ++ 127 KIF7-001 + ++ 128 KIF1B-002 + ++ 129MAPK6-001 + ++ 130 ASPM-002 + +++ 131 SMC4-001 + ++

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1. A peptide or a variant peptide comprising an amino acid sequenceselected from the group consisting of SEQ ID No. 1 to SEQ ID No. 49, SEQID No. 71, and SEQ ID No. 74 to 129, and variant sequences thereof whichare at least 90% homologous to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No.71, and SEQ ID No. 74 to 129, and wherein a variant induces T cellscross-reacting with said variant peptide; and/or a pharmaceuticalacceptable salt thereof, wherein said peptide is not a full-lengthpolypeptide.
 2. The peptide or variant peptide according to claim 1,wherein said peptide or variant peptide maintains an ability to bind toa molecule of the human major histocompatibility complex (MHC) class-Ior -II, and wherein said peptide or variant peptide is capable ofstimulating CD4 and/or CD8 T cells.
 3. The peptide or variant peptideaccording to claim 1, wherein the amino acid sequence thereof comprisesa continuous stretch of amino acids according the group of SEQ ID No. 1to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to
 129. 4. Thepeptide or variant peptide according to claim 1, wherein said peptide orvariant thereof has an overall length of from 8 to 100, optionally from8 to 30, and/or optionally from 8 to 16 amino acids, and/or optionallywherein the peptide consists or consists essentially of an amino acidsequence according to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, andSEQ ID No. 74 to
 129. 5. The peptide or variant peptide according toclaim 1, wherein said peptide or variant peptide is modified and/orincludes non-peptide bonds.
 6. The peptide or variant peptide accordingto claim 1, wherein said peptide or variant peptide is part of a fusionprotein, optionally comprising N-terminal amino acids of the HLA-DRantigen-associated invariant chain (Ii).
 7. A nucleic acid, encoding apeptide or variant peptide according to claim 1, optionally linked to aheterologous promoter sequence.
 8. An expression vector capable ofexpressing the nucleic acid according to claim
 7. 9. The peptide orvariant peptide according to claim 1, capable of being used in medicine.10. A host cell comprising the nucleic acid according to claim 7,wherein said host cell optionally is an antigen presenting cell or adendritic cell.
 11. A method for producing the peptide or variantpeptide according to claim 1, the method comprising culturing a hostcell that expresses a nucleic acid or an expression vector, andisolating the peptide or variant peptide from the host cell or a culturemedium.
 12. An in vitro method for producing activated cytotoxic Tlymphocytes (CTL), the method comprising contacting in vitro CTL withantigen loaded human class I or II MHC molecules expressed on thesurface of a suitable antigen-presenting cell or an artificial constructmimicking an antigen-presenting cell for a period of time sufficient toactivate said CTL in an antigen specific manner, wherein said antigen isa peptide or variant according to claim
 1. 13. An activated cytotoxic Tlymphocyte (CTL), produced by an in vitro method for producing activatedcytotoxic T lymphocytes (CTL), the method comprising contacting in vitroCTL with antigen loaded human class I or II MHC molecules expressed onthe surface of a suitable antigen-presenting cell or an artificialconstruct mimicking an antigen-presenting cell for a period of timesufficient to activate said CTL in an antigen specific manner thatselectively recognises a cell which aberrantly expresses a polypeptidecomprising an amino acid sequence of a peptide or variant peptide ofclaim
 1. 14. A method for killing target cells in a patient which targetcells aberrantly express a polypeptide comprising an amino acid sequenceof a peptide or variant peptide of claim 1, the method comprisingadministering to the patient an effective number of cytotoxic Tlymphocytes (CTL).
 15. An antibody that specifically recognizes thepeptide or variant peptide according to claim 1 optionally wherein thepeptide or variant peptide is bound to an MHC molecule.
 16. A peptide orvariant peptide according to claim 1, capable of being used fortreatment of cancer or in the manufacture of a medicament againstcancer, wherein said medicament optionally is a vaccine.
 17. The peptideor variant peptide according to claim 16, wherein said cancer isselected from astrocytoma, pilocytic astrocytoma, dysembryoplasticneuroepithelial tumor, oligodendrogliomas, ependymoma, glioblastomamultiforme, mixed gliomas, oligoastrocytomas, medulloblastoma,retinoblastoma, neuroblastoma, germinoma, teratoma, gangliogliomas,gangliocytoma, central gangliocytoma, primitive neuroectodermal tumors(PNET, e.g. medulloblastoma, medulloepithelioma, neuroblastoma,retinoblastoma, ependymoblastoma), tumors of the pineal parenchyma (e.g.pineocytoma, pineoblastoma), ependymal cell tumors, choroid plexustumors, neuroepithelial tumors of uncertain origin (e.g. gliomatosiscerebri, astroblastoma), glioblastoma prostate tumor, breast cancer,esophageal cancer, colorectal cancer, clear cell renal cell carcinoma,lung cancer, CNS, ovarian, melanoma pancreatic cancer, squamous cellcarcinoma, leukemia medulloblastoma, colon, rectum, stomach, kidney,lung, pancreas, prostate, skin and other tumors which show anoverexpression of PTPRZ1, BCAN, and/or FABP7 and/or another protein fromwhich a peptide of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQID No. 74 to 129 is derived from.
 18. A kit comprising: (a) a containercomprising a pharmaceutical composition containing the peptide orvariant peptide according to claim 1 in solution or in lyophilized form;(b) optionally, a second container containing a diluent orreconstituting solution for the lyophilized formulation; (c) optionally,at least one more peptide selected from the group consisting of SEQ IDNo. 1 to SEQ ID No. 131, and (d) optionally, instructions for (i) use ofthe solution or (ii) reconstitution and/or use of the lyophilizedformulation.
 19. The kit according to claim 18, further comprising oneor more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle,or (v) a syringe.
 20. The kit according to claim 18, wherein saidpeptide or variant peptide is selected from the group consisting of SEQID No. 1 to SEQ ID No. 19, SEQ ID No. 42 to 44, SEQ ID 50 to SEQ ID 65and SEQ IDs No. 71 to SEQ ID
 88. 21. A method for producing apersonalized anti-cancer vaccine for an individual patient, said methodcomprising: a) identifying tumor-associated peptides (TUMAPs) presentedby a tumor sample from the individual patient; b) comparing the peptidesas identified in a) with a warehouse of peptides that have beenprescreened for immunogenicity and overpresentation in tumors ascompared to corresponding normal tissue; c) selecting at least onepeptide from the warehouse that correlates with a tumor-associatedpeptide identified in the patient; and d) manufacturing the personalizedvaccine based on step c).
 22. The method according to claim 21, whereinsaid TUMAPs are identified by: a1) comparing expression data from thetumor sample to expression data from a sample of normal tissuecorresponding to the tissue type of the tumor sample to identifyproteins that are over-expressed or aberrantly expressed in the tumorsample; and a2) correlating the expression data with sequences of MHCligands bound to MHC class I and/or class II molecules in the tumorsample to identify MHC ligands derived from proteins over-expressed oraberrantly expressed by the tumor.
 23. The method according to claim 21,wherein the sequences of MHC ligands is identified by eluting boundpeptides from MHC molecules isolated from the tumor sample, andsequencing the eluted ligands.
 24. The method according to claim 21,wherein the normal tissue corresponding to the tissue type of the tumorsample is obtained from the patient.
 25. The method according to claim21, wherein the peptide or variant peptide included in the warehouse isidentified according to: a. HLA ligands from the malignant material areidentified by mass spectrometry; b. Genome-wide messenger ribonucleicacid (mRNA) expression analysis by microarrays is used to identify genesover-expressed in the malignant tissue (GBM) compared with a range ofnormal organs and tissues; c. The identified HLA ligands are compared togene expression data; d. Peptides encoded by selectively expressed orover-expressed genes as detected in step b are selected; e. therelevance of over-expression at the mRNA level is confirmed byredetection of selected TUMAPs from step c on tumor tissue and lack ofor infrequent detection on healthy tissues; and f. To assess whether aninduction of in vivo T-cell responses by the selected peptides isfeasible, in vitro immunogenicity assays will performed using human Tcells from healthy donors or the patient.
 26. The method according toclaim 21, wherein the immunogenicity of the peptide or variant peptideincluded in the warehouse is determined by a method comprising in vitroimmunogenicity assays, patient immunomonitoring for individual HLAbinding, MHC multimer staining, ELISPOT assays and/or intracellularcytokine staining.
 27. The method according to claim 21, wherein saidwarehouse comprises a plurality of peptides or variant peptides selectedfrom the group consisting of SEQ ID No 1 to SEQ ID No
 131. 28. Themethod according to claim 21, further comprising d) identifying at leastone mutation that is unique to the tumor sample relative to normalcorresponding tissue from the individual patient, and selecting apeptide for inclusion in the vaccine that correlates with the mutation.29. The method of claim 28, wherein said at least one mutation isidentified by whole genome sequencing.
 30. A T-cell receptor that isreactive with an HLA ligand having at least 80% identity to an aminoacid sequence selected from the group consisting SEQ ID No. 1 to SEQ IDNo. 49, SEQ ID No. 71, and SEQ ID No. 74 to
 129. 31. The T-cell receptoraccording to claim 30, wherein said amino acid sequence is to least 90%,or to at least 95% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ IDNo. 71, and SEQ ID No. 74 to
 129. 32. The T-cell receptor according toclaim 30, wherein said amino acid sequence comprises any SEQ ID No. 1 toSEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to
 129. 33. The T-cellreceptor according to claim 30, wherein said amino acid sequenceconsists of any of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQID No. 74 to
 129. 34. A fusion protein, comprising (a) an amino acidsequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No.49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and (b) N-terminal aminoacids 1-80 of HLA-DR antigen-associated invariant chain (Ii).
 35. Thefusion protein according to claim 34, wherein said amino acid sequenceof (a) is at least 90%, optionally at least 95% identical to SEQ ID No.1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to
 129. 36. Thefusion protein according to claim 35, wherein said amino acid sequenceof (a) comprises SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQID No. 74 to
 129. 37. A nucleic acid, encoding for: (a) the peptide orvariant peptide according to claim 1; (b) a T cell receptor that isreactive with an HLA ligand having at least 80% identity to an aminoacid sequence selected from the group consisting SEQ ID No. 1 to SEQ IDNo. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; or (c) a fusion proteincomprising (a) an amino acid sequence that is to at least 80% identicalto SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to129; and (b) N-terminal amino acids 1-80 of HLA-DR antigen-associatedinvariant chain (Ii).
 38. The nucleic acid according to claim 37, whichis DNA, cDNA, PNA, RNA, or combinations thereof.
 39. An expressionvector comprising a nucleic acid according to claim
 37. 40. A host cellcomprising the nucleic acid according to claim 37, or an expressionvector thereof.
 41. The host cell according to claim 40 that is anantigen presenting cell, optionally a dendritic cell.
 42. A method forproducing (a) the peptide or variant peptide according to claim 1; or(b) the T cell receptor that is reactive with an HLA ligand having atleast 80% identity to an amino acid sequence selected from the groupconsisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No.74 to 129 or (c) a fusion protein comprising: an amino acid sequencethat is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQID No. 71, and SEQ ID No. 74 to 129; and N-terminal amino acids 1-80 ofHLA-DR antigen-associated invariant chain (Ii), said method comprisingculturing a host cell, and isolating said peptide or variant peptide,said T cell receptor, or said fusion protein from said host cell and/orculture medium.
 43. An in vitro method for producing activated cytotoxicT lymphocytes (CTL), the method comprising contacting in vitro a CTLwith antigen loaded human class I or II MHC molecules expressed on thesurface of a suitable antigen-presenting cell for a period of timesufficient to activate said CTL in an antigen specific manner, whereinsaid antigen is said peptide or variant peptide according to claim 1.44. The method according to claim 43, wherein said antigen is loadedonto class I or II MHC molecules expressed on the surface of a suitableantigen-presenting cell by contacting a sufficient amount of the antigenwith an antigen-presenting cell.
 45. The method according to claim 44,wherein said antigen-presenting cell comprises an expression vectorcapable of expressing said peptide or variant peptide according toclaim
 1. 46. An activated cytotoxic T lymphocyte (CTL), produced by themethod according to claim
 44. 47. A method of killing target cancercells in a patient, the method comprising administering to said patientan effective number of cytotoxic T lymphocytes (CTL) according to claim46.
 48. A peptide or variant peptide according to claim 1, a T cellreceptor that is reactive with an HLA ligand having at least 80%identity to an amino acid sequence selected from the group consistingSEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129,a fusion protein comprising: an amino acid sequence that is to at least80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQID No. 74 to 129; and N-terminal amino acids 1-80 of HLA-DRantigen-associated invariant chain (Ii), a nucleic acid, an expressionvector a host cell, or an activated cytotoxic T lymphocyte capable ofbeing used as a medicament, and/or in the manufacture of a medicament.